AU726075B2 - 6-o-substituted erythromycin compounds and method for making same - Google Patents

Abstract

Antimicrobial compounds having formula (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX); as well as the pharmaceutically acceptable salts, esters and prodrugs thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of the compounds.

Description

6-O-Substituted Erythromycin Compounds and Method for Making Same Technical Field The present invention relates to novel semisynthetic macrolides having antibacterial activity and useful in the treatment and prevention of bacterial infections. More particularly, the invention relates to 6-O-substituted erythromycin derivatives, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.

Background of the Invention Erythromycins A through D, represented by formula

CH

3 NMe 2 0* OH 2

CH

3 CH3 i HO O CH 3 Erythromycin K' R 12 H H A -OH -CH 3

H

3 C" CH,3,,,CH 3 B -H -CH 3

CH

3 CH H C -OH -H CH3 CH3

C

0 CH 3 O H D -H -H oOR'

(I)

are well-known and potent antibacterial agents, used widely to treat and prevent bacterial infection. As with other antibacterials, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to 15 identify new erythromycin derivative compounds which possess improved antibacterial activity, which have less potential for developing resistance, which possess the desired Gram-negative activity, or which possess unexpected selectivity against target [N:\LIBXX]01070:MEF WO 97/42206 PCT/US97/07702 W microorganisms. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity.

Morimoto et al. described the preparation of 6-0-methyl erythromycin A in J.

Antibiotics 37:187 (1984). Morimoto et al. further disclosed a series of O-alkyl erythromycin A derivatives in J. Antibiotics 43: 286 (1990). In their experience, "0alkylation, other than methylation, took place at the C- 1 hydroxyl group exclusively." However, in European Patent Application 272,110, published June 22, 1988, Morimoto et al. disclose 6-O-C 1 -C3-alkyl erythromycin A compounds.

In European Patent Application 215,355, published March 28, 1987, Omura and Itoh disclose 6-O-loweralkyl erythromycins as stimulants of gastrointestinal contractile motion.

Summary of the Invention The present invention provides a novel class of 6-O-substituted erythromycin compounds which possess antibacterial activity.

In one aspect of the present invention is disclosed a novel 6-O-substituted erythromycin compound selected from the formulae:

(II);

-2- 0 0 o0

'(AD

'(III)

4 ZOLLOL6SflIJJ 9~'L P 90ZZV/L6 OAt WO 97/42206 I0 0*0 Rbh Re

(VI);

01 Rb 0,, 0

R

(VII);

D

E R

A

B 6 0 Rb 0 0, 0

F

(VII); and PCTIUS97/07702 -4- WO 97/42206 PCTfUS97/07702 D H N R R NMe 2 B 6 0 0 I?~~Rc 0d

(IX);

as well as the pharmaceutically acceptable salts, esters and prod rugs thereof. In formulae (11) (IX) above, X is selected from the group consisting of =0,

=N-OH,

=N-0-RI where RI is selected from the group consisting of unsubstituted Cl-C 1 2-alkyl,

CI-C

12 -alkyl substituted with aryl, CI-C 1 2-allcyl substituted with substituted aryl, CI-Cl2-alkyl substituted with heteroaryl, CI-C12-alkyl substituted with substituted heteroaryl,

C

3 -C 12 -cycloalkyl, -Si-(R 2

)(R

3

)(R

4 wherein R 2

R

3 and R 4 are each independently selected from C 1 -C12-alkyl, and -Si-(Aryl)3; and =N-0-C(R 5

)(R

6 where RI is as defined above and R 5 and R 6 are each independently selected from the group consisting of hydrogen, unsubstituted

CI-C

1 2-alkyl,

CI-C

1 2-alkyl substituted with aryl,

CI-C

1 2-alkyl substituted with substituted aryl, CI-C12-alkyl substituted with heteroaryl, and WO 97/42206 PCTIU-S97/07 702

CI-C

1 2-alkyl substituted with substituted heteroaryl,

R

5 and R 6 taken together with the atom to which they are attached form a

C

3

-C

12 -cycloalkyl ring; Ra is hydrogen or hydroxy; Rb is hydrogen or hydroxy; one of RC and Rd is hydrogen and the other of Rc and Rd is selected from the group consisting of hydroxy, protected hydroxy, halogen,

NR

7

R

8 where R 7 and R 8 are independently selected from the group consisting of hydrogen, Cl-C 1 2-alkyl, substituted C 1

-C

1 2-alkyl, Cl-C8-cycloalkyl, substituted CI-C 8 -cycloalkyl,

CI-C

1 2-alkyl substituted with aryl,

CI-C

1 2-alkyl substituted with substituted aryl,

CI-C

1 2-alkyl substituted with heterocycloalkyl,

CI-C

1 2-alkyl substituted with substituted heterocycloalkyl, CI-C12-alkyl substituted with CI-C8-cycloalcyl, CI-C12-alkyl substituted with substituted Cl-C8-cycloalkyl,

CI-C

1 2-alkyl substituted with heteroaryl, and (in) Cl-C 1 2-alkyl substituted with substituted heteroaryl, or

R

7 and R 8 taken together with the atom to which they are attached form a 3- 10 membered heterocycloalkyl ring, O-CO-NH-aryl, O-CO-NH-heteroaryl,

O-CO-NR

7

R

8 where R 7 and R 8 are as defined above,

O-SO

2 -Cl-C6-alkyl, -6- WO 97/42206 PCT/US97/07702 W O-SO 2 -(substituted C 1

-C

6 -alkyl), and O-S0 2

-CH

2 -CH2-NR 7

R

8 where R 7 and R 8 are as defined above, or Rc and Rd taken together form the grouping selected from the group consisting of =0,

=N-OH,

and

=N-OR

1 wherein R 1 is as defined above;

R

e is methoxy, fluorine or hydroxy;

R

f is hydrogen or a hydroxy protecting group; W is absent or selected from the group consisting of -NH-CO-, -N=CH- and -NH-; Rg is selected from the group consisting of hydrogen,

C

1

-C

6 -alkyl optionally substituted with one or more substituents selected from the group consisting of aryl, substituted-aryl, heteroaryl, substituted-heteroaryl, hydroxy,

C

1

-C

6 -alkoxy,

NR

9

R

10 where R 9 and R 10 are independently selected from hydrogen and C 1

-C

6 -alkyl, or R 9 and R 10 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of -N(C1-C6-alkyl-)-, -N(aryl)-, -N(aryl-C1-C6-alkyl-)-, -N(substituted-aryl-C1-C6-alkyl-)-, -N(heteroaryl)-, -N(heteroaryl- C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl-)-, and or wherein n is 1 or 2, and -CH2-M-R 11 -7fi J WO 97/42206 PCTIUS97/07702 wherein M is selected from the group consisting of: Wi (ii) (iii) -NH-, (iv) -N(CH3)-, (vi) -NH-C(O)-O- (vii) -NH-C(O)-NH- (viii) -O-C(O)-NH- (ix) (x (xi) wherein n is 0, 1 or 2, (xii) (xiii) and (xiv) and RI I is selected from the group consisting of: Wi CI-C 6 -alkyl, optionally substituted with a substituent selected from the group consisting of (aa) aryl, (bb) substituted-aryl, (cc) heteroaryl, and (dd) substituted-heteroaryl, (ii) aryl, (iii) substituted-aryl, (iv) heteroaryl, substituted-heteroaryl, and (vi) heterocycloalkyl,

C

3 -C7-cycloalkyl, aryl, substituted- aryl, heteroaryl, and substituted-heteroaryl; -8- W0O97/42206 PCTIUS97/07702 Rb is selected from the group consisting of hydrogen, hydroxy, -O-C(O)-imidazolyl,

-O-C(O)-O-CI-C

6 -alkyl, -O-C(O)-O-aryl, -O-C(O)-O-(substituted aryl), and R is selected from the group consisting of methyl substituted with a moiety selected from the group consisting of

CN,

F,

-C0 2

RI

2 wherein R 12 is C 1 -C3-alkyl or aryl substituted CI-C 3 ailkyl, or heteroaryl substituted CI-C3-alkyl, S(O)nR 12 where n is 0, 1 or 2 and R 12 is as defined above,

NI-C(O)RI

2 where R 12 is as defined above,

NHC(O)NR

13

RI

4 wherein R 13 and R 14 are independently selected from hydrogen and Cl-C 3 -alkyl, (2) (3) group aryl, substituted aryl, Wi heteroaryl, and substituted heteroaryl,

C

2 -C 1 o-alkyl,

C

2 -Clo-alkyl substituted with one or more substituents selected from the consisting of halogen, hydroxy, CI-C3-alkoxy, C 1 -C3-alkoxy-C 1

-C

3 -alkoxy, oxo,

-N

3

-CHO,

O-S 02- (substituted CI-C6-alkyl), WO 97/42206 PCTfUS97/07702 0 Wi -NR 15

R

16 wherein R 15 and R 16 are selected from the group consisting of hydrogen, (ii) CI-C 1 2-alkyi, (iii) substituted Cl-C12-alkYl, (iv) Ci-C 1 2-alkenyl, substituted Cl-Ci2-aikenyl, (vi) Ci -C 2-aikynyl, (vii) substituted CI-C12-alkynyl, (viii) aryl, (ix) C 3 -C8-cycloalkyl, substituted C 3 -C8-cycloalkyi, (xi) substituted aryl, (xii) heterocycloalkyl, (xiii) substituted heterocycloalkyl, (xiv) CI-C12-alkyl substituted with aryl, (xv) Cl-C 1 2-alkyl substituted with substituted aryl, (xvi) CI-Cl2-alcyl substituted with heterocycloalkyl, (xvii) CI-Ci2-alkyl substituted with substituted heterocycloalkyl, (xviii) ClI-C 1 2-alkyl substituted with C 3 -Cg-cycloalkyl, (xix) CI-C 1 2-alkyl substituted with substituted C 3 -C8-cycloalkyl, (xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) CI-Cl2-alkyl substituted with heteroaryl, and (xxiii) CI-C 1 2-alkyl substituted with substituted heteroaryl, or

R

15 and R 16 are taken together with the atom to which they are attached form a 3- 10 membered heterocycloalkyl ring which may be substituted with one or more substituents independently selected from the group consisting of halogen, (ii) hydroxy, (iii) CI-C3-alkoxy, (iv) CI-C3-alkoxy-C i-C3-alkoxy, oxo, (vi) CI-C3-alkyl, 10 WO 97/42206 PCT[US97/07702 0 (vii) halo-C 1 -C3-alkyl, and (vii) Cl-C 3 -alkoxy-C1-C3-alkyl, -C0 2

RI

2 wherein

R

12 is as defined above,

-C(O)NR

13

RI

4 wherein R 13 and R 14 are as defined above,

=N-O-R

12 wherein R 13 is as previously defined, (in) -C=NN, O-S(O)npR 12 wherein n is 0, 1 or 2 and R 12 is as defined above, aryl, substituted aryl, heteroaryl, substituted heteroaryl,

C

3

-C

8 -cYcloalkyl, (t substituted

C

3 -C8-cycloalkyl,

CI-C

1 2-alkyl substituted with heteroaryl, heterocycloalcyl, substituted heterocycloalkyl,

NHC(O)RI

2 where R 12 is as previously defined,

NHC(O)NR

13

RI

4 wherein R 13 and R 14 are as previously defined,

=N-NR

15 Rl 6 wherein R 15 and R 16 are as previously defined, (aa) -N-R 1 I wherein RII is as previously defined, (bb) =N-NHC(O)RI 2 wherein R 12 is as previously defined.

and (cc) =N-NHC(O)NR 13

RI

4 wherein R 13 and R 14 are as previously defined;

C

3 -alkenyl substituted with a moiety selected from the group consisting of halogen,

-CHO,

-C0 2

RI

2 where R 12 is as defined above, -C(O)-Rl I where R 1 I is as defined above,

-C(O)NR

13

RI

4 wherein R 13 and R 14 are as previously defined, aryl, substituted aryl, heteroaryl, substituted heteroaryl,

C

3

-C

7 -cycloalkyl, -1I1I- WO 97/42206 PCT/US97/07702 and Cl-C 1 2-alkyl substituted with heteroaryl,

C

4 -Clo-alkenyl;

C

4 -Clo-alkenyl substituted with one or more substituents selected from the group consisting of halogen,

CI-C

3 -alkoxy, oxo,

-CHO,

-C0 2

R

12 where R 12 is as defined above,

-C(O)NR

13

RI

4 wherein R 13 and R 14 are as previously defined,

-NR

15

R

16 wherein R 15 and R 16 are as previously defined,

=N-O-R

12 where R 12 is as previously defined, Wi

-C=EN,

O-S(O)nRI 2 where n is 0, 1 or 2 and R 12 is as previously defined, aryl, substituted aryl, (in) heteroaryl, substituted heteroaryl,

C

3

-C

7 -cycloalkyl,

CI-C

1 2-alkyl substituted with heteroaryl,

NHC(O)RI

2 where R 12 is as previously defined,

NHC(O)NR

13

RI

4 wherein R 13 and R 14 are as previously defined.

=N-NR

15

R

16 wherein R 15 and R 16 are as previously defined, =N-RI I wherein R I is as previously defined,

=N-NHC(O)RI

2 where R 12 is as previously defined, and

=N-NHC(O)NR'

3

RI

4 wherein R 13 and R 14 are as previously defined;

C

3 -Clo-alkynyl; and

C

3 -Clo-alkynyl substituted with one or more substituents selected from the group consisting of trialkylsilyl, aryl, substituted aryl, heteroaryl, 12 WO 97/42206 PCT/US97/07702 and substituted heteroaryl; one of Y and Z is hydrogen and the other is selected from a group consisting of hydrogen, hydroxy, protected hydroxy, and

NR

7

R

8 wherein R 7 and R 8 are as defined above; and A, B, D and E, with the provision that at least two of A, B, D and E are hydrogen, are independently selected from the group consisting of: hydrogen;

C

1 -C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of: aryl; (ii) substituted-aryl; (iii) heteroaryl; (iv) substituted-heteroaryl; heterocycloalkyl; (vi) hydroxy; (vii) C1-C 6 -alkoxy; (viii) halogen consisting of Br, Cl, F or I; and (ix) NR 9

R

10 wherein R 9 and R 10 are as defined above;

C

3

-C

7 -cycloalkyl; aryl; substituted-aryl; heteroaryl; substituted-heteroaryl; heterocycloalkyl; and a group selected from option above further substituted with -M-R 11 wherein M and R 11 are as defined above; or any one pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7- 13- WO 97/42206 PCT/US97/07702 membered ring optionally containing a hetero function selected from the group consisting of-O-, -N(CI-C6-alkyl-)-, -N(aryl-C1-C6-alkyl-)-, -N(substituted-aryl-C1-C 6 -alkyl-)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C 6 -alkyl-)-, or wherein n is 1 or 2, -C(O)-NR 12 wherein R 12 is as defined above,

-NR

12 wherein R 12 is as defined above, and In another aspect of the present invention are disclosed pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier and treatment of antibacterial infections with such compositions. Suitable carriers and methods of formulation are also disclosed. The compounds and compositions of the present invention have antibacterial activity.

In a further aspect of the present invention are provided processes for the preparation of 6-O-substituted macrolide derivatives of Formula (III), (VII), (VM) and (IX) above.

Detailed Description of the Invention One embodiment of the present invention comprises a compound of formula (II) above, wherein X, R, R a Rb, Rc, Rd, Re and R f are as defined above.

Another embodiment of the present invention comprises a compound of formula (III) above, wherein Y, Z, R, R a Rb, Rc, Rd, Re and R f are as defined above.

Another embodiment of the present invention comprises a compound of formula (IV) above, wherein R, Rb, R c Rd, R e and R f are as defined above.

Another embodiment of the present invention comprises a compound of formula (V) above, wherein R, Rb, R c Rd, Re and R f are as defined above.

Another embodiment of the present invention comprises a compound of formula (VI) above, R, Rb, Rc, Rd R e

R

f and Rh, are as defined above.

-14- WO 97/42206 PCT/US97/07702 0 Another embodiment of the present invention comprises a compound of formula (VII) above, wherein W, R, Rb, Rc, R d

R

e Rf and Re are as defined above.

Another embodiment of the present invention comprises a compound of formula (VIII) above, wherein A, B, D, E, R, Rb, Rc, Rd, Re and R f are as defined above.

Another embodiment of the present invention comprises a compound of formula (IX) above, wherein A, B, D, E, R, Rb, R c

R

d Re and R f are as defined above.

A preferred embodiment of the present invention is the compound of formula S R NMe 2

(X)

where X and R are as defined above.

Another preferred embodiment of the present invention is the compound of formula

(XI):

Y R NMe2 6 HO 0 O, O OMe

(XI)

where X and R are as defined above.

Another preferred embodiment of the present invention is the compound of formula

(XI):

v R NMe 2 Z I HO, 6 HO 0

(XI)

WO 97/42206 PCT/US97/07702 where Y, Z and R are as defined above.

A preferred intermediate in the preparation of the compound of formula is the compound of formula (XII) S H RP NMe 2 O 04

HO

o 0,, 0 Me

(XII)

where X is as defined above and RP is a hydroxy protecting group.

A compound according to Claim 1 which is selected from the group consisting of: compounds wherein A, B, D, E, W, X, Y, Z, R, R a Rb, R c Rd, R e Rf, Rg and Rh are as previously defined, and R is selected from the group consisting of: (1) (2) (3) (4)

C

-16- PCTIUS97/07702 WO 97/42206

OCH

3

CN

(9)

CO

2 CHb 10(11) (12) o 0 (13) Si (14) (16) OH 3 (17)

MN

(18)

(I

(19) 17 WO 97/42206 PCT/US97/07702

N

-I

N

(21) (22) (23) (24)

NO

2

OCH

3 o 0" o'CH 3 (26) Y1/ NH 2 (27) 0 (28) o

~CH

3 (29) o (31) o o ;and

H

(32) Br compounds wherein Ra is OH; Rb is H; Rc is H; Rd is H; R e is methoxy; R f is H; wherein R is selected from the group consisting of: -18- WO 97/42206 PCTIUS97/07702

OH

H

(3)OH

H

SN~. OH 3

OH

3 N CH 3

L"

~yNH 2 0

NH

2

H

0

JOH

3

H

,0 ThH 3 (~10) 011) C H 3

OH

3 (12)

O

3

OH

3 (13) O01- H 3 0% 0H 3

CH

(15) o S. H (16) 1 19 WO 9742206PCT/US97/07702 0 .H (18) (19)

NCH

3 (21) (22) 0 (23) NO 2 (24) C i.

OCH

3 (26) CN; (27) C2F (28)

CH

3 (29)

H

CH

3 0p0 PCT[US97/07702 O WO 97/42206 sK (32)

CH

3 (33) (34)OH

IK-

5(36)MN (37)

N

(38) (39) NO

OCH

3 (40)0 (41)CH 3 Y NH 2 (42)0 (43)0 21 WO 97/42206 PCT/US97/07702 0

YCH

3 (44) o (46) o ;and

H

(47) a compound of Formula (II) therein wherein X is Rb is H; Rc is H; Rd is acetyl; Re is methoxy; R f is acetyl; R is -CH2-CH=CH2; a compound of Formula therein which is selected from the group wherein Rb is H; R c is H; Rd is phenylmethyloxycarbonyl; Re is methoxy; Rf is H; R is -CH2-CH=CH2; and

R

b is H; R c is H; Rd is hydroxy; Re is methoxy;

R

f is H; R is -CH2-CH=CH2; a compound of Formula (VI) therein which is selected from the group wherein Rb is H; Rc is H; Rd is phenylmethyloxycarbonyl; Re is methoxy; Rf is acetyl; R is -CH2-CH-CH2; and Ra is hydroxy; Rb is H; Rc is H; Rd is H; Re is methoxy; R f is H; R is -CH2-CH=CH2; a compound of Formula (VII) therein which is selected from the group wherein W is -NH-;Rb is H; R c is H; Rd is phenylmethyloxycarbonyl; Re is methoxy; R f is H; Rg is H; R is propyl; W is Rb is H; RC is H; Rd is H; Re is methoxy;

R

f is H; Rg is H; R is propyl; W is Rb is H; R c is H; R d is phenylmethyloxycarbonyl; Re is methoxy; R f is H; Rg is H; R is -CH2-CH=CH2; -22- PCTIUS97/07702 WO 97/42206 0 W is absent; Rb is H; Rc is H; Rd is phenylmethyloxycarbonyl; Re is methoxy; Rf is acetyl; Rg is 4-phenylbutyl; R is -CH2-CH=-CH2; W is absent; Rb is H; RC is H; Rd is phenylmethyloxycarbonyl; Re is methoxy; Rf is H; Rg is 4-phenylbutyl; R is -CH2-CH--CH2; W is absent; Rb is H; Rc is H; Rd is H; Re is methoxy; Rf is H; Rg is 4-phenylbutyl; R is propyl; W is absent; Rb is H; Rc is H; Rd is phenylmethyloxycarbonyl; Re is methoxy; Rf is acetyl; Rg is 4-phenylbutyl; R is -CH2-CH=-CH2-(3quinolinyl); W is absent; Rb is H; Rc is H; Rd is phenylmethyloxycarbOflyl; Re is methoxy; Rf is H; Rg is 4-phenylbutyl; R is -CH2-CH--CH2-(3quinolinyl); W is absent; Rb is H; RC is H; Rd is H; Re is methoxy; Rf is H; Rg is 4-phenylbutyl; R is -CH 2 -CH2-CH2-(3-quinolinyl); (10) W is absent; Rb is H; RC is H; Rd is H; Re is methoxy; Rf is H; Rg is H; R is -CH2-CH=CH2; (11) W is absent; Rb is H; Rc is H; Rd is H; Re is methoxy; Rf is H; Rg is H; R is propyl; (12) W is absent; Rb is H; Rc is H; Rd is H; Re is methoxy; Rf is H; Rg is H; R is -CH2-C(O)-H; (13) W is absent; Rb is H; Rc is H; Rd is H; Re is methoxy; Rf is H; Rg is H; R is -CH2-C=N-O-CH2-pheny1; (14) W is absent; Rb is H; Rc is H; Rd is H; Re is methoxy; Rf is H; Rg is H; R is -CH 2 -CH2-NH-CH2-phenyl; (15) W is absent; Rb is H; RC is H; Rd is H; Re is methoxy; Rf is H; Rg is H; R is -CH2-C=N-O-H (anti-isomer); (16) W is absent; Rb is H; Rc is H; Rd is H; Re is methoxy; Rf is H; Rg is H; R is -CH2-C=N-O-H (syn-isomer); (17) W is absent; Rb is H; Rc is H; Rd is H; Re is methoxy; Rf is H; Rg is H; R is -CH2-C=N-O-pheny1; (18) W is absent; Rb is H; Rc is H; Rd is H; Re is methoxy; Rf is H; Rg is H; R is -CH 2 -C=N-O-CH2-(4-nitrophenyl); (19) W is absent; Rb is H; RC is H; Rd is H; Re is methoxy; Rf is H; Rg is H; R is -C2CN0C2(4qioiy) (20) W is absent; Rb is H; RC is H; Rd is H; Re is methoxy; Rf is H; Rg is H; R is -CH2-C=N-O-C(phenY1)3 23 WO 97/42206 PCTIUS97/07702 (21) W is absent; Rb is H; RC is H; Rd is H; Re is methoxy; Rf is H; Rg is H; R is -CH2-CH2-NH2 (22) W is absent; Rb is H; RC is H; Rd is H; Re is methoxy; Rf is H; Rg is H; R is -CH 2 -CH2-NH-CH2-phenyl; (23) W is absent; Rb is H; RC is H; Rd is H; Re is methoxy; Rf is H; Rg is H; R is -C2C2N-H2C2pey (24) W is absent; Rb is H; Rc is H; Rd is H; Re is methoxy; Rf is H; Rg is H; R is -C2C2N-H-H-H-hnl W is absent; Rb is H; Rc is H; Rd is acetyl; Re is methoxy; Rf is acetyl; Rg is H; R is -CH2-CH--CH2; (26) W is absent; Rb is H; Rc is H; Rd is acetyl; Re is methoxy; Rf is acetyl; Rg is H; R is -CH 2 -CH=CH2-(3-quinolinyl); (27) W is absent; Rb is H; Rc is H; Rd is acetyl; Re is methoxy; Rf is H; Rg is H; R is -CH 2 CH=CH2-(3-quinolilyl); (28) W is absent; Rb is H; Rc is H; Rd is H; Re is methoxy; Rf is H; Rg is H; R is -CH 2 CH=CH2-(3-quinolilyl); (29) W is absent; Rb is H; Rc is H; Rd is H; Re is methoxy; Rf is acetyl; Rg is H; R is -CH 2 CH-CH-(3-quinoilyl); W is absent; Rb is H; RC is H; Rd is methoxy; Re is methoxy; Rf is H; Rg is H; R is -CH 2 CH-CH-(3-quinoflyl); (31) W is absent; Rb is H; Rc is H; Re is methoxy; Rd is ethenesulfonyloxy; Rf is acetyl; Rg is H; R is -CH2CH-CH2-(3quinolinyl); (32) W is absent; Rb is H; RC is H; Re is methoxy; Rd is 2- (dimethylamino)ethylsulfofloxy Rf is acetyl; Rg is H; R is

-CH

2 CH=CH2-(3-quinolinyl); (33) W is absent; Rb is H; Rc is H; Rd is inethoxy; Re is 2- (phenylthio)ethoxy; Rf is acetyl; Rg is H; R is -CH2CH-CH2-(3quinolinyl); (34) W is absent; Rb is H; RC is H; Rd is methoxy; Re is (2nitrophenyl)aminocarbonyloxy; Rf is H; Rg is H; R is -CH2CH=CH2-(3-quinoilyl); and W is absent; Rb is H; RC is H; Rd is inethoxy; Re is nitrophenyl)aminocarbonyloxy; Rf is H; Rg is H; R is CH2CH=CH2-3-quililyl); -24 WO 97/42206 PCTIUS97/07702 0 a compound wherein Ra' is OH; Rb is H; RC is H; Rd is H; Re is methoxy; Rf is H; selected from the group consisting of compounds wherein X is R is -CH 2 -CH=CH2-(3-quinolilyl); X is R is allyl; X is =N-OH, R is allyl; X is R is propyl; .X is R is 2,3-dihydroxypropyl; X is R is 2,3-epoxypropyl; X is R is 2-hydroxy-3-(imidazo- 1 -yl)propyl; X is R. is 2-hydroxy-3-(morphofl-4-yl)propyl; X is R is 2-hydroxy-3-(benzylamilo)propyl; X is R is 2-oxoethyl; (11) X is R is 2-oxopropyl; (12) X is =N-O-(l-isopropoxycyclohexyl), R is -CH2-CJCH; (13) R is -CH 2 -CJCH, X is =N-O-H; (14) X is R is -CH2-CJCH; X is R is -CH 2 -CHOH-CH2-N3; (16) X is R is (17) X is R is -CH2-CH2OH; (18) X is R is -CH2-CH2NH2; (19) X is R is -CH2-CN; X is R is -CH2-Phenyl; (21) X is R is -CH2-CH=-CH-Phenyl-; (22) X is R is -CH2-CH=N-0-CH3; (23) X is R is -CH 2 -CH=N-0-CH2-Phenyl; (24) X is R is -CH 2 -CH=N-N(CH3)2; X is R is -CH 2 -CH=N-NH(CH3); (26) X is R is -CH 2 -CH=N-(4-Morpholinyl); (27) X is R is -CH 2 -CH=N-NH(Phenyl); and (28) X is R is -CH 2 -CH=N-N(Phenyl)2; (29) X=0, R=Phenylpropyl; X=0, R is -CH 2 CH=CH-(4-methy1phelyl); (31) X=0, R is -CH 2 -CH(0H)-Phenyl; (32) X=0, R is -CH2-CH(Br)-CH2Br; (33) X=0, R is -CH 2

CH

2 NHCH2CH2CH2-Phenyl; (34) X=0, R is -CH 2

CH

2 NHCH(CH2Phenyl)C02Me; 25 WO 97/42206 PCT1US97/07702 0(35) X0O, R is -CH 2 CH2NHCH2CH2CH3; (36) X0O, R is -CH 2

CH

2 NHCH2C02CH2CH2; (37) X=0, R is -CH 2

CH

2 N11CH2CH2-Phenyl; (38) X0O, R is -CH 2

CH

2 NHCH2CH2-(4-hydroxyphenyl); (39) X=0, R is -CH 2

CH

2 NHCH2CH2-(3-hydroxyphenyl); X=O, R is -CH 2

CH

2 NHCH2CH2-(3methoxyphelyl); (41) X=O, R is -CH 2

CH

2 NHCH2CH2(2methoxyphel); (42) X=O, R is -CH 2

CH

2 NI1CH2CH2-(4-methoxyphenyl); (43) X=O, R is -CH 2 CH2NHCH2-pheny1; (44) X is =N-O-(-isopropoxycyc1ohexyl), R is fluoromethyl; X=O, R is -CH 2

CH

2 NHCH2CH2-(3-chlorophelyl); (46) X0O, R is -CH 2

CH

2 NHCH2CH2-(2-chlorophelyl); (47) X=O, R is -CH 2

CH

2 NI-CH2CH2-(4-chlorophelyl); (48) X=O, R is -CH 2 CH2NHCH2CH2-O-pheflyl); (49) X=O, R is -CH 2

CH

2 NHCH2CH2CH2-(4-quinolinyl); X=O, R is -CH 2

CH

2 NHCH2CH2CH2-(3quinoinyl); (51) X=O, R is -CH 2

CH

2 NHCH2CH2CH2CH2-phenyl; (52) X=O, R is -CH 2 -CH=N-N1--C(O)-NH2; (53) X=O, R is -CH 2 -CH=N-NH-(2-pyridinyl); (54) X=O, R is -CH 2 -CH=N-(4-methylpiperazinyl); X=O, R is -CH 2 -CH=N-O-pheny1; (56) X0O, R is -CH 2 CH(OH)CH2NHCH2CH2-phenyl; (57) X=O, R is -CH 2 CH(OH)CH2N1CH2-(4-pyridil; (58) X is R is (3-iodophenyl)methyl; and (59) X is R is (4-fluorophenyl)methyl, a compound wherein Ra is OH; Rb is H; Rc is H; Rd is H; Re is methoxy; Rf is H; X is 0; R is CH 2 -CH(OH)-CH2-RV ;and RV is selected from the group consisting of: (1)21 (2) (3) (4) 26 SUBSTITUTE SHEET (RULE 26) PCTIUS97/07702 WO 97/42206 0

OH

N

(7) (8)

NJ

(12) (13)

\CPO~

(14) N r k

N

(16)\0 (17) (19) N (21) OMe (22) n 27 SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 (23) (24) (26)

OCF

3 (27) (28) (29) 0r(

OH

(31) "cl; (32)

OH

OH

(33) (34) o 0;

OH

(36) OMe OMe (37) (38) (39) N 28 SUBSTITUTE SHEET (RULE 26) PCT[IJS97/07702 WO 97/42206 (41) (42) (43) (44) <rQ (45) \fi- CN; OMe Ki~ 0 o Oe (46) ,N% k'4) ~~2OMe (47) QOMe (48) OMe (49) rC Y (50) f4 ,c"c (51) (52) XrN.) F (53) (54) rN) -29- SUBSTITUTE SHEET (RULE 26) PCT/US97/07702 WO 97/42206 0 (56) (57)

OH

(58) r-"

^N--N

(59) (60) N> (61) (62) (63) (64) (65) ,--c.OMe r, (66)

N

(67) (68) (69) (70) (71) SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 (72) (73) Cl (74) (76) OMe (77)

F

(78) a aFn; and r~/oz (79) a compound wherein X is O, R is CH2-CH2-RW,and

R

W is selected from the group consisting of: (1) (2)

O

Me (4) (6) (7) -31- SUBSTITUTE SHEET (RULE 26) PCTIS97/07702 WO 97/42206 rNulaCF 3 cN2 (9)

F~-

(12)

F

(13) (14) OMe (16) O KrQ ~~2CN (17) (18) (19) (21) -32- SUBSTITUTE SHEET (RULE 26) PCTIUS97/07702 WO 97/42206 OMe (22) (23) (24)

NO

2 JaQ (26) ajfCF3 (27) (28) N) SMe (29)0 (31) OI e OMe (32) pF (33)

Q

(34) MN. F.

-33- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/U97/07702 (36) 0N.

(37) (38) cI r' N Cl (39) \N-2 (40) 1 r~ lWC OMe (41) (42) 0 (43) Ci (44) (46) OMe OMe (47) eand (48) -34- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT1US97/07702 0(j) a compound wherein X is 0, R is CH 2 -CH=N-RX, and RX is selected from the group consisting of: (2) (3)

H

N

(6)

N

(8)

H

o21 N0 2 0 ;and (11) 0 and a compound wherein Ra' is OH; Rb is H; Rc is H; Rd is RP; Re is methoxy; Rf is RP; selected from the group consisting of compounds wherein: X is =N-O-(l-isopropoxycycohexyl), R is allyl, RP is Trimethylsilyl X is =N-O-(1-isopropoxycyc1ohexyl), R is -CH2-Phenyl, RP is Trimethylsilyl; X is =N-O-(l-isopropoxycyclohexyl), R is -CH2-Phenyl, RP is H; and X is =N-OH, R is -CH2-Phenyl, RP is H; and pharmaceutically acceptable salts, esters and prodrugs therof.

Preferred compounds are those selected from the group consisting of a compound wherein Ra is OH; Rb is H; Rc is H; Rd is H; Re is methoxy; Rf is H; selected from the group consisting of compounds wherein X is R is -CH 2 -CH=CI-2-(3-quinolinyl); 35 SUBSTITUTE SHE ET (RULE 26) WO 97/42206 PCTIUS97/07702 X is R is allyl; X is =N-OH, R is allyl; X is R is propyl; X is R is 2,3-dihydroxypropyl; X is R is 2,3-epoxypropyl; X is R is 2-hydroxy-3-(imidazol-1-yl)propyl; X is R is 2-hydroxy-3-(morpho11fl- 4 -yl)propyl; X is R is 2-hydroxy-3-(belnaio)propyl; X is R is 2-oxoethyl; (11) X is R is 2-oxopropyl; (12) X is =N-0-(1-isopropoxycyclohexyl), R is -CH2-CJCH; (13) R is -CH-2-CICH, X is =N-0-H; (14) X is R is -CH2-CJCH; X is R is -CH 2 -CHOH-CH2-N3; (16) X is R is -CH2-CH=N-OH; (17) X is R is -CH2-CH2OH; (18) X is R is -CH2-CH2NH-2; (19) X is R is -CH2-CN; X is R is -CH2-Phenyl; (21) X is R is -CH 2 -CH=CH-Pheny1-; (22) X is R is -CH 2 -CH=N-0-CH3; (23) X is R is -CH 2 -CH=N-0-CH2-Pheny1; (24) X is R is -CH 2 -CH=N-N(CH3)2; X is is -CH2-CH=N-NH(CH3); (26) X is R is -CH 2 -CH=N-(4-Morpholinyl); (27) X is R is -CH 2 -CH=N-NH(Phenyl); and (28) X is R is -CH2-CH=N-N(PhenY1)2; (29) X=0, R=Phenylpropyl; X=0, R is -CH 2 CH=CH-(4-methylphel); (31) X=0, R is -CH 2 CH(0H)-Phenyl; (32) X=0, R is -CH 2 -CH(Br)-CH2Br; (33) X=0, R is -CH 2 CH2NHCH2CH2CH2-Phenyl; (34) X=0, R is -CH 2

CH

2 NHCH(CIA2PhenYI)CO2Me; X=0, R is -CH 2 CH2NHCH2CH2CH3; (36) X0O, R is -CH 2 CH2NHCH2C02CH2CH2; (37) X=0, R is -CH 2

CH

2 N1{CH2CH2-Phenyl; (38) X=0, R is -CH 2

CH

2

NHCH

2 CH2-(4-hydroxyphenyl); 36 .WO 97/42206 PCTIUS97/07702 (39) X=0, R is -CH2CH2NHCH2CH2..(3..hydroxyphenyl); X0O, R is -CH2CH2NHCH2CH2.(3methoxyphenyl); (41) X=0, R is -CH2CH2NHCH2CH2.(2-.methoxyphenyl); (42) X=O, R is -CH2CH2NHCII2CH2.(4methoxyphenyl); (43) X=O, R is -CH2CH2NHCH 2 -pheny1; (44) X is =N-O-(l-isopropoxycyc1,ohexyl), R is fluoromethyl; X=O, R is -CH2CH2NACH 2

CH

2 -chiorophenyl); (46) X=O, R is -CH2CH2NHCH2CH 2 -(2-chlorophenyI); (47) X=O, R is -CH2CH2NHCH2CH2.(4-.chlorophenyl); (48) X=0, R is -CH2CH2NHCH 2

CH

2 .0-phenyl); (49) X=O, R is -CH2CH2NHCH2CH2CH 2 .(4-quinolinyl); X=0, R is -CH2CH2NHCH2CH2CH 2 .(3..quinolinyl); (51) X=O, R is -CH2CH2NHCH2CH2CH 2

CH

2 -pheIyl; (52) X=O, R is -CH2-CH=N-NH-.C(O).N} 2 (53) X=O, R is -CH2-CH=N.N-H(2-.pyridinyl); (54) X=O, R is -CH2-CH=N-(4-methylpiperaziny1); X=0, R is -CH2-CH=N-O-phenyl; (56) X=O, R is -CH2CH(0H)CH2NHCH 2

CH

2 -phenyl; (57) X=0, R is -CH2CH(OH)CH2NAfCH 2 (4-pyidlyl; (58) X is R is 3 -iodophenyl)methyl; and (59) X is R is 4 -fluoropheny)methyl; (B3) a compound wherein Ra is OH; Rb is H; RC is H; Rd is H; Re is methoxy; Rf is H; X is 0; R is CH2-CH(OH)-CH 2 -RV ;and RV is selected from the group consisting of- 25(1 00 (2) (3)

\-O

OH

(6) SUBSTITUTE SHEET (RULE 26) PCT/US97/07702 WO 97/42206 (8) NN r-s

N";

(11) (12) A (13) (14) r N (16) (17) (18) (19)

F

(21) "c o OMe (22) 5 O (23)

N

(24) -38- SUBSTITUTE SHEET (RULE 26) PCTIUS97/07702 WO 97/42206 (26)

CF

3 (27) Q (28) (29)

OH

(31)CI (32) Xr-OH

OH

(33) (34) (36)

O

r'OMe (37) O, e (38) h 15(39) N cJ 39 SUBSTITUTE SHEET (RULE 26) PCTfUS97/07702 WO 97/42206

K-

(42) (43) (44)

CN;

OMe (46) N-0 (48) OMe N'lOMe (48) (49) (51) NN> (52)

F

K-N

(53) (54) .N) (56) SUBSTITUTE SHEET (RULE 26) PCT/US97/07702 WO 97/42206 (57)

OH

(58) rN i (59) x (61)

OH

(62) (63) (64) OMe (66) (67) (68) rI"' (69) (71) c (72) (73) .Cl; -41 SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 0 (74) \1N 0 (76) OMe (77)

F

(78) F; and (79) a compound wherein X is O, R is CH 2 -CH2-RW, and R W is selected from the group consisting of: (1)

O

Me.

I c-0; (6) (7)

(*N-CF

3

F;

-42- SUBSTITUTE SHEET (RULE 26) PCT[US97/07702 WO 97142206 (12)

F

(13) (14) OMe (16) O (17) ON; (18) "cuh) (19) C (21) (22) (23) -43- SUBSTITUTE SHEET (RULE 26) PCTfUS9707702 WO 97/42206 (24) rl N'lr N0 (26) cl 4l" F 3 (27) (28) SMe.

(29) 02 (31) (32) OMe OMe ~qF (33) (34) r (36)

N)

(37) -44- SUBSTITUTE SHEET (RULE 26) PCT/US97/07702 WO 97/42206 0 (38) N cl;

N

cl

&L'

(39) (41) (42) cI 1 r-N OMe

CI

Cl

K^NI&

yr(N) (43) (44) (46) OMe OOMee (47) ;and (48) and a compound wherein X is O, R is CH 2 -CH=N-RX, and RX is selected from the group consisting of: (1) (2) (3) SUBSTITUTE SHEET (RULE 26) PCTIUS97/07702 WO 97/42206 0 H

N

(6) (7)

H

02

NR

0 ;and (11) 0 as well as the pharmaceutically acceptable salts, esters and prodrugs thereof.

More preferred compounds are selected from the group consisting of: Compound of Formula WX: Compound of Formula Compound of Formula Compound of Formula (X: Compound of Formula (X: Compound of Formula Compound of Formula WX: Compound of Formula X is R is -CH 2 -CH=CH2-(3-quinolinyl); X is R is allyl; X is R is 2-hydroxy-3-(benzylamino)propyl; X is R is 2-oxopropyl; X is R is -CH 2 -c-'CH; X is R is -CH 2

-CH=N-OH;

X is R is -CH 2

-CH

2 0H; X is R is -CH 2

-CH

2 NII2; and Compound of Formula X is R is -CH 2

-CN;

as well as the pharmnaceutically acceptable salts, esters and prodrugs thereof.

46 SUBSTITUTE SHEET (RULE 26) WO 9742206PCT1US97/07702 A process for the preparation of 6-0-substituted inacrolide derivatives having the Formulae: Rf NMe 2 x 0R HO0,, 6 0"0 Rb 0, 0 R 0 Rc R Rf NMe 2 zag.R IQ H Ra 0 0 Rb 0 0,

CIII);

0Rf NMe 2 6 01"., 00 R b 0 0

R

(IV);

47 PCTIUS97/07702 WO 97/42206 0 RfR NMe 2 0 R I 6 0 0 0 Rbc o RfR NMe 2 004 R h 0 R b 0 011".R~ 0

RR

(VI);

RfR NM wg 0,RI, 00 0 R e

(VIII);

-48 PCT1US97107702 WO 97/42206 0 (VIII); and

(IX);

wherein X is selected from the group consisting of =0,

=N-OH,

=N-0-Rl where RI is selected from the group consisting of unsubstituted C 1

-C

12 -alkyl, CI-Ct-alkyl substituted with aryl,

CI-C

12 -alkyl substituted with substituted aryl,

CI-C

1 2-alkyl substituted with heteroaryl,

CI-C

12 -alkyl substituted with substituted heteroaryl,

C

3

-C

12 -cycloalkyl, -Si-(R 2

)(R

3

)(R

4 wherein R 2

R

3 and R 4 are each independently selected from Cl-C12-alkyl, and 49 PCT1US97/07702 WO 97/42206 -Si-(Aryl)3; 1 5

=N-O-C(R

5

)(R

6 where RI is as defined above and R 5 and R 6 are each independently selected from the group consisting of hydrogen, unsubstituted Cl-C 1 2-alkyl, Cl-C 1 2-alkyl substituted with aryl, CI-C12-alkyl substituted with substituted aryl, Cl-C 1 2-alkyl substituted with heteroaryl, CI-C l2-alkyl substituted with substituted heteroaryl,

R

5 and R 6 taken together with the atom to which they are attached form a

C

3 -C 2-cycloalkyl ring; Ra is hydrogen or hydroxy; Rb is hydrogen or hydroxy; one of RC and Rd is hydrogen and the other of Rc and Rd is selected from the group consisting of hydroxy, protected hydroxy, halogen,

NR

7

R

8 where R 7 and R 8 are independently selected from the group consisting of hydrogen, substituted Cl-C12-alkYl, Cl-C 8 -cycloalkyl, substituted Cl-C8-cycloalkyl,

CI-C

1 2-alkyl substituted with aryl, Cl-C 1 2-alkyl substituted with substituted aryl, Cl-C 1 2-alkyl substituted with heterocycloallcyl, Wi CI-C12-alkyl substituted with substituted heterocycloalkyl, CI.C12-alkyl. substituted with C 1 -C8-cycloalkyl, Cl-C 12-alkyl substituted with substituted C 1

-C

8 -cycloalky 1, PCTIUS97/07702 WO 97/42206 0 C1-C 1 2-alkyl substituted with heteroaryl, and C1-C12-alkyl substituted with substituted heteroaryl, or

R

7 and R 8 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, O-CO-NH-aryl, O-CO-NH-heteroaryl,

O-CO-NR

7

R

8 where R 7 and R 8 are as defined above, O-S0 2 -C1-C6-alkyl,

O-SO

2 -(substituted C1-C6-alkyl), and

O-SO

2

-CH

2

-CH

2

-NR

7

R

8 where R 7 and R 8 are as defined above, or Rc and Rd taken together form the grouping selected from the group consisting of =0,

=N-OH,

and

=N-OR

1 wherein R 1 is as defined above; Re is methoxy, fluorine or hydroxy;

R

f is hydrogen or a hydroxy protecting group; W is absent or selected from the group consisting of -NH-CO-, -N=CH- and -NH-; Rg is selected from the group consisting of hydrogen,

C

1 -C6-alkyl optionally substituted with one or more substituents selected from the group consisting of aryl, substituted-aryl, heteroaryl, substituted-heteroaryl, hydroxy,

C

1

-C

6 -alkoxy, -51- WO 97/42206 PCT/US97/07702

NRIO

1 where R 9 and R 10 are independently selected from hydrogen and Cl-C6-alkyl, or R 9 and RIO are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of -N(C 1

-C

6 -alkyl-)-, -N(aryl)-, -N(aryl-CI-C6-alkyl-)-, -N(substituted-aryl-C 1 .C6-alkyl-)-, -N(heteroaryl)-, -N(heteroaryl- CI-C6-alkyl-)-, -N(substituted-heteroaryl-Cl-C6-aClkyl)- and or wherein n is 1 or 2, and

-CH

2

-M-R

1 wherein M is selected from the group consisting of: Wi (ii) (iii) -NH-, (iv) -N(CH3)-, (vi) -NH-C(0)-O- (vii) -NH-C(0)-NH- (viii) -O-C(O)-NH- (ix) (xi) wherein n is 0, 1 or 2, (xii) (xiii) and (xiv) and RI I is selected from the group consisting of: Wi CI-C6-alkyl, optionally substituted with a substituent selected from the group consisting of (aa) aryl, (bb) substituted-aryl, (cc) heteroaryl, and (dd) substituted-heteroaryl, (ii) aryl, (iii) substituted-aryl, 52- PCT1US97/07702 WO 97/42206 0 (iv) heteroaryl, substituted-heteroalyl, (3) (4) (6) and (7) and (vi)

C

3

-C

7 -cycloalkyl, aryl, substituted-aryl, heteroaryl, heterocycloalkyl, substituted-heteroaryl; Rh is selected (1) (2) (3) (4) (6) (7) (8) R is selected (1) from the group consisting of hydrogen, hydroxy, -O-C(O)-O-aryl, -O-C(O)-O-(substituted aryl), and -O-C(O)-NH2; from the group consisting of methyl substituted with a moiety selected from the group consisting of

CN,

F,

-C0 2

RI

2 wherein R 12 is CI-C 3 -alkyl or aryl substituted CI-C3 ~-alkcyl, or heteroaryl substituted

CI-C

3 -alkyl, S(O)nRI 2 where n is 0, 1 or 2 and R 12 is as defined above,

NHC(O)RI

2 where R 12 is as defined above, NHC(O)NR1 3

RI

4 wherein R 13 and R 14 are independently selected from hydrogen and Cl-C 3 -alkyl, aryl, substituted aryl, heteroaryl, (g) (h) and substituted heteroaryl,

C

2 -CIO-alkyl, -53- PCTIUS97/07702 WO 97/42206

C

2 -Clo-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, CI-C3-alkoxy,

CI-C

3 alkoxy-C-C3-alkoxy, oxo, -N3,

-CHO,

0- S0 2 (substituted

CI-C

6 -alkyl), Wi -NR 15

R

16 wherein

R

15 and R 16 are selected from the group consisting of Wi hydrogen, (ii) Cl-C 1 2-alkyl, (iii) substituted

CI-C

1 2-alkyl, (iv) C 1

-C

12 -alkenyl, substituted

CI-C

12 -alkenyl, (vi) CI-C 1 2-alkynyl, (vii) substituted

CI-C

12 -alkynyl, (viii) aryl, (ix)

C

3

-C

8 -cycloalkyl, substituted

C

3 -C8-CYcloalkyl, (xi) substituted aryl, (xii) heterocycloalkyl, (xiii) substituted heterocycloalkyl, (xiv) CI-C 1 2-alkyl substituted with aryl, (xv) CI-C 12 -alkyl substituted with substituted aryl, (xvi) CI-C 12 -alkyl substituted with heterocycloalkyl, (xvii) CI-C 12 -alkyl substituted with substituted heterocycloalkyl, (xviii) CI-C 1 2-alkyl substituted with C 3

-C

8 -cycloalkyl, (xix) CI-C12-alkyl substituted with substituted

C

3 -C8-cycloalkyl, (xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) C I-C 1 2-alkyl substituted with heteroaryl, and (xxiii) CI-C 12 -alkyl substituted with substituted heteroaryl, 54- PCTIUS97107702 WO 97/42206 0

R

15 and R 16 are taken together with the atom to which they are attached form a 3- 10 membered heterocycloalkyl ring which may be substituted with one or more substituents independently selected from the group consisting of halogen, (ii) hydroxy, (iii) CI-C3-alkoxy, (iv) C 1

-C

3 -alkoxy-C 1

-C

3 -alkoxy, oxo, (vi) C 1 -C3-alkyl, (vii) halo-Cl-C3-alkyl, and (vii) Ci -C 3 -alkoxy-C 1

-C

3 -alkyl, -C0 2

RI

2 wherein R 12 is as defined above,

-C(O)NR

13

RI

4 wherein R 13 and R 14 are as defined above, =N-0-R 12 wherein R 13 is as previously defined, (in) O-S(O)nRI 2 wherein n is 0, 1 or 2 and R 12 is as defined above, aryl, substituted aryl, heteroaryl, substituted heteroaryl,

C

3 -C8-cycloalkyl, Wt substituted

C

3 -C8-cycloalkyl,

CI-C

1 2-alkyl substituted with heteroaryl, heterocycloalkyl, substituted heterocycloalkyl,

NHC(O)RI

2 where R 12 is as previously defined,

NHC(O)NR

13

RI

4 wherein R 13 and R 14 are as previously defined,

=N-NR

15 Rl 6 wherein R 15 and R 16 are as previously defined,

=N-R

1 I wherein R I is as previously defined, (bb) =N-NHC(O)Rl 2 wherein R 12 is as previously defined, and (cc) =N-NHC(O)NR 13

RI

4 wherein R 13 and R 14 are as previously defined;

C

3 -alkenyl substituted with a moiety selected from the group consisting of halogen, 55 WO 97/42206 PCT/EJS97/07702

-CHO,

-C0 2

RI

2 where R 12 is as defined above, -C(O)-RI I where RI I is as defined above, -C(O)NR1 3

R

1 4 wherein R 1 3 and R 14 are as Previously defined, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C3-C7-cycloalkyl, and CI-C12-alkyl substituted with heteroaryl,

C

4

-C

1 o-allcenyl; C4-Cio-alkenyl substituted with one or more substituents selected from the group consisting of halogen, CI-C3-alkoxy, oxo,

-CHO,

-C0 2

RI

2 where R 12 is as defined above, -C(O)NR 1 3 R 14 wherein R 13 and R 14 are as previously defined, -NR I 5 R 16 wherein R 15 and R 16 are as previously defined, =N-0-R 12 where R 12 is as previously defined, O-S(O)nRI 2 where n is 0, 1 or 2 and R 12 is as previously defined, aryl, substituted aryl, (in) heteroaryl, substituted heteroaryl, C3-C7-cycloalkyl, Cl-C12-alkyl substituted with heteroaryl,

NHC(O)RI

2 where R 12 is as previously defined, NHC(O)NR

I

3 R 14 wherein R 13 and R 14 are as previously defined,

=N-NR

15

RI

6 wherein R 15 and R 16 are as previously defined, =N-R I wherein R I is as previously defined,

=N-NHC(O)RI

2 where R 12 is as previously defined, and 56 WO 97/42206 PCT/US97/07702

=N-NHC(O)NR

13

R

14 wherein R 13 and R 14 are as previously defined;

C

3 and

C

3 -Co1-alkynyl substituted with one or more substituents selected from the group consisting of trialkylsilyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; one of Y and Z is hydrogen and the other is selected from a group consisting of hydrogen, hydroxy, protected hydroxy, and

NR

7

R

8 wherein R 7 and R 8 are as defined above; and A, B, D and E, with the provision that at least two of A, B, D and E are hydrogen, are independently selected from the group consisting of: hydrogen;

C

1

-C

6 -alkyl, optionally substituted with one or more substituents selected from the group consisting of: aryl; (ii) substituted-aryl; (iii) heteroaryl; (iv) substituted-heteroaryl; heterocycloalkyl; (vi) hydroxy; (vii) C 1

-C

6 -alkoxy; (viii) halogen consisting of Br, Cl, F or I; and (ix) NR 9

R

10 wherein R 9 and R 10 are as defined above;

C

3

-C

7 -cycloalkyl; -57- WO 97/42206 PCTTJS97IO7702 0(e) substituted-aryl; heteroaryl; substituted-heteroaryl; heterocycloalkyl; and a group selected from option above further substituted with -M-R 1

I,

wherein M and R 11 are as defined above; or any one pair of substituents, consisting of A-B, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7membered ring optionally containing a hetero function selected from the group consisting of-O-, -N(CI -C 6 -alkyl-)-, -N(aryl-CI -C 6 -alkyl-)-, -N(substituted-aryl-C1-C6-alkyl-)-, -N(heteroaryl-Cl-C6-alkyl-)-, -N(substituted-heteroaryl-Cl-C6-alkyl-)-, or wherein n is 1 or 2,

-C(O)-NR

12 wherein R 12 is as defined above,

-NR

12 wherein R 12 is as defined above, and is a method comprising: treating a compound having the formulae H Rp NMe 2 H RP NMe 2 IZoo..

I

Ra 0 0 Ra 0 Rb 0 ".0b 0 0 Rc0 58 PCT1US97/07702 WO 97/42206

S

Rg

V

I,

Rb 59 PCTIUS97/07702 WO 97/42206 wherein RP is a hydroxy protecting group and V is -N-O-RI or =N-O-C(R 9

)(RIO)-O-RI

wherein R 1

R

9 and RIO are as defined above, with a base in an aprotic solvent then with an alkylating agent to give a compound having the formula RP NM, 2 0 0 Rc 60 PCT/US97/07702 WO 97/42206

RP

or iN Rc wherein A, B, D, E, W, X, Y, Z, Ra, Rb, Rc, Rd, Re, Rf, R9 and Rh are as defined above, V is =N-O-Rl or =N-O-C(R 5

)(R

6 )-O-RI wherein RI, R 5 and R 6 are as defined above, and R. is the "alkyl group" derived from the corresponding alkylating agent; deprotecting the and 4'-hydroxyl groups to give a compound of the formula -61- PCTIUS97/07702 WO 97/42206

OH

R 4NMe 2 N R

Z

6 HO,, 6

R

Ra 0 Rb FII C, H Rbj 0 A Re

OH

H NMe 2 R R O 04, Ot 0 C pb 0Rb RO

H

RC

Re

OHO

IH H NM0 2 Rg NIR I

I

6 oc Rh 0 0 Rl R b 0 R 0,R 0 0 "1

R

-62- PCTIUS97/07702 WO 97/42206

)-H

or wherein A, B, D, E, W, X, Y, Z, Ra, Rb, RC, Rd, Re, Rf, Rg and Rh are as defined above and R is the "alkyl group" derived from the corresponding alkylating agent; and deoximation with an inorganic sulfur oxide salt or an inorganic nitrite salt in the presence of acid in a suitable solvent to give the desired products.

A preferred process for the preparation of 6-O-substituted macrolide compounds of the invention is the process immediately above wherein in step the base is selected from the group consisting of potassium hydroxide, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride, potassium hydride, potassium isopropoxide, potassium tertbutoxide and potassium isobutoxide, the alkylating agent is selected from the group consisting of allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, 4nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, oa-bromo-ptolunitrile, cinnamyl bromide, methyl 4-bromocrotonate, crotyl bromide, 1-bromo-2pentene, 3-bromo-l-propenyl phenyl sulfone, 3-bromo-l-trimethylsilyl-l-propyne, 3- -63 WO 97/42206 PCT/US97/07702 bromo-2-octyne, l-bromo-2-butyne, 2-picolyl chloride, 3-picolyl chloride, 4-picolyl chloride, 4-bromomethyl quinoline, bromoacetonitrile, epichlorohydrin, bromofluoromethane, bromonitromethane, methyl bromoacetate, methoxymethyl chloride, bromoacetamide, 2-bromoacetophenone, 1-bromo-2-butanone, bromo chloromethane, bromomethyl phenyl sulfone, 1,3-dibromo-l-propene, allyl O-tosylate, 3-phenylpropyl-Otrifluoromethane sulfonate, and n-butyl-O-methanesulfonate, and the reaction is performed at a temperature from about -15 OC to about 50 "C for a period from 0.5 hours to 10 days; In the preferred process in step deprotection is accomplished by use of acetic acid in water and acetonitrile.

In the preferred process in step the deoximating reagent is an inorganic sulfur oxide compound is selected from the group consisting of sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, sodium dithionate, potassium thiosulfate, and potassium metabisulfite, or an inorganic nitrite salt in the presence of acid selected from the group consisting of sodium nitrite and potassium nitrite, and the solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, trimethylsilanol or a mixture of one or more thereof.

A preferred process of the invention is a process as described above for the preparation of 6-O-substituted macrolide compounds having formula (II) thereof wherein in step the starting compound of has the formula S H RP NMe 2 V 1 I o

S..

6 4 HO 0 0 RP 0OMe wherein RP is trimethylsilyl and V is a ketone protecting group and it is treated with potassium hydroxide in a mixture of THF and DMSO, in step deprotection of the and 4'-hydroxyl groups is accomplished using acetic acid in water and acetonitrile to give a compound having the formula -64- WO 97/42206 PCT/US97/07702 OH I R H NMe 2 N I HO,, 6 HO 0 0

-H

OMe In this preferred process in step the 9-oxime is deoximinated using NaHSO3 and formic acid in ethanol-water.

In a more preferred process for the preparation of 6-O-substituted macrolide compounds having the formula having formula in step RP is trimethylsilyl and the ketone protecting group is O-(1-isopropoxycyclohexyl) oxime.

Definitions The terms "C1-C 1 2-alkyl" as used herein refer to saturated, straight- or branchedchain hydrocarbon radicals containing between one and twelve carbon atoms. Examples of

C

1

-C

3 alkyl radicals include methyl, ethyl, propyl and isopropyl, and examples of C 1

-C

6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tertbutyl, neopentyl and n-hexyl.

The term "C 1

-C

6 -alkoxy" as used herein refers to an CI-C 6 -alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.

Examples of C 1

-C

6 -alkoxy, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.

The term "acylamino" as used herein refers to a C 1

-C

6 -alkyl, aryl, or substituted aryl group attached to the amino group via a carbonyl grouping. Examples of acylamino include, but are not limited to acetylamino, trifluoroacetylamino, propanoylamino, benzoylamino, 4-chlorbenzoylamino, and the like.

The term "alkenyl" as used herein refers to a branched or straight hydrocarbon chain comprising two to ten carbon atoms which also comprises one or more carbon-carbon double bonds. Representative alkenyl groups include 2-propenyl allyl), 3-methyl-2butenyl, 3,7-dimethyl-2,6-octadienyl, 4,8-dimethyl-3,7-nonadienyl, 3,7,11-trimethyl- 2,6,10-dodecatrienyl and the like.

WO 97/42206 PCT/US97/07702 The term "alkynyl" as used herein refers to a branched or straight hydrocarbon chain comprising two to ten carbon atoms which also comprises one or more carbon-carbon triple bonds. Representative alkynyl groups include ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.

The term "C 1

-C

3 -alkyl-amino" as used herein refers to one or two C1-C 3 -alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. Examples of C 1

-C

3 -alkyl-amino include, but are not limited to methylamino, dimethylamino, ethylamino, diethylamino, and propylamino.

The term "aprotic solvent" as used herein refers to a solvent that is relatively inert to proton activity, not acting as a proton-donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chlorofom, and the like, heteroaryl compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A.

Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley Sons, NY, 1986.

The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups (including bicyclic aryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, acylamino, cyano, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.

The term "C 3

-C

12 -cycloalkyl" as used herein refers to carbocyclic groups of 3 to 12 carbons, respectively, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term "C1-C 3 -alkyl-C3-C5-cycloalkyl", as used herein refers to a cycloalkyl radical, as defined above, attached to a C 1

-C

3 -alkyl radical by replacement of a hydrogen atom on the latter.

-66- WO 9742206PCT1US97/07702 0 The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.

The term "heteroaryl", as used herein, refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, 0 and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, 0 and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.

The term "heterocycloalkyl" as used herein, refers to a non-aromatic partially unsaturated or fully saturated 3- to lO-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- or nri-cyclic ring systems which may include aromatic sixmembered aryl or heteroaryl rings fused to a non-aromatic ring. These heterocycloalkyl rings include those having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatermized.

Representative heterocycloalkyl rings include, but are not limited to, oxiranyl, aziranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrazolinyl, pyrazolidinyl, piperazinyl, azacycloheptanyl, azacyclooctanyl, 1 ,4-diazacycloheptaflyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

Specific heterocycloalkyl rings contained in the examples below include: 3-methyl- 4 (3-methylphenyl)piperazine, 3-methylpiperidine, 4-(bis-(4fluorophenyl)methyl)piperazine, 4-(diphenylmethyl)piperazine, 4-(ethoxycarbonyl)piperazine, 4- (ethoxycarbonylmethyl)piperazine, 4-(phenylmethyl)piperazine, 1phenylethyl)piperazine, 1,1 -dimethylethoxycarbonyl)piperazine, 4-(2-(bis-(2propenyl)amino)ethyl)piperazine, 4-(2-(diethylarnino)ethyl)piperazine, 4-(2chlorophenyl)piperazine, 4-(2-cyanophenyl)piperazine, 4-(2-ethoxyphenyl)piperazine, 4-(2ethylphenyl)piperazlne, 4-(2-fluorophenyl)piperazifle, 4-(2-hydroxyethyl)piperazifle, 4-(2methoxyethyl)piperazine, 4-(2-methoxyphenyl)piperazine, 4-(2-methylphenyl)piperazine, 4- (2-methylthiophenyl)piperazine, 4-(2-nitrophenyl)piperazine, 4-(2-nitrophenyl)piperazine, 4-(2-phenylethyl)piperazine, 4-(2-pyridyl)piperazine, 4-(2-pyrimidinyl)piperazine, 4-(2,3dimethylphenyl)piperazine, 4-(2,4-difluorophenyl)piperazine, 4-(2,4dimethoxyphenyl)piperazifle, 4-(2,4-dimethylphenyl)piperaie, 4-(2,5dimethylphenyl)piperazine, 4- (2,6-dimethylphenyl)piperazine, 4-(3chlorophenyl)piperazifle, 4-(3-methylpheny1)piperazine, 4-(3trifluoromethylphenyl)piperazine, 4-(3 ,4-dichlorophenyl)piperazine, 4-(3,4- -67 WO 97/42206 PCTIUS97/07702 dimethoxypheflyl)piperazine, 4 -(3,4-dimethylpheflyl)piperazine, 4-(3,4methylenedioxypheflyl)piperazine, 4-(3 ,4,5-trimethoxypheflyl)piperazine, 4-(3,5dichloropheflyl)piPerazine, 4-(3 ,5-dimethoxyphefl)piperazine, 4-(4- (phenylmethoxy)phel)piperazine, 1, l-dimethylethyl)phelylmethylDpiperazine, 4-(4chloro-3-trifluoromethylphenylDpiperazine, 4-(4-chlorophenyl)-3-methylpiperazine, 4-(4chlorophenyl)piPerazlfle, 4-(4-chloropheflyl)piperazine, 4-(4chloropheflylmethyl)piperazine, 4-(4-fluoropheny)pipeazifle, 4-(4methoxyphelyl)Piperazifle, 4-(4-methylpheflyl)piperazine, 4-(4-nitrophel)piperazifle, 4- (4-trifluoromethylphel)piperazine, 4-cyclohexylpiperazifle, 4-ethylpiperazifle, 4-hydroxy- 4-(4-chloropheny)methylpipefldine, 4-hydroxy-4-phefllpiperidine, 4-hydroxypyrolidifle, 4-methylpiperazine, 4-phenylpiperazifle, 4-piperidinylpiperazifle, furanyl)carbonyl)piperazifle, 1, 3 -dioxolafl-5-yl)methylpiperazine, 6-fluoro- 1,2,3,4tetrahydro-2-methylquifloline, 1 ,4-diazacyc1oheptanfe, 2,3-dihydroindolyl, 3,3dimethylpiperidifle, 4,4-ethylenedioxypiperidifle, 1,2,3 ,4-tetrahydroisoquifline, 1,2,3,4tetrahydroquinoline, azacyclooctalC, decahydroquiflolifle, piperazine. piperidine.

pyrrolidine. thiomorpholine. and triazole.

"Hydroxy-protecting group", as used herein, refers to an easily removable group which is known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable. The use of hydroxy-protectiflg groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, cf, for example.

T.H.

Greene and P.G.M. Wuts, Protective roups in Organic Synthesis 2nd edition, John Wiley Sons, New York (199 Examples of hydroxy-proteciflg groups include, but are not limited to, methylthiomethyl, tert-dimethylsilyl, tert-butyldipheflylsilyl, acyl substituted with an aromatic group and the like.

The term "ketone protecting group", as used herein, refers to an easily removable group which is known in the art to protect a ketone group against undesirable reactions during synthetic procedures and to be selectively removable. The use of ketone-proteting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, cf, for example,

T.H.

Greene and P.G.M. Wuts, Protective Groups in ranic nthesis. 2nd edition, John Wiley Sons, New York (1991). Examples of ketone-protecting groups include, but are not limited to, ketals, oximes, 0-substituted oximes for example O-benzyl oxime, 0phenyithiomethyl oxime, i-isopropoxycyclohexyl oxime, and the like.

A the term "protected-hydroxy" refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.

68 WO 97/42206 PCT/US97/07702 0 The term "protogenic organic solvent" as used herein refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley Sons, NY, 1986.

The term "substituted aryl" as used herein refers to an aryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C1-C3-alkyl, CI-C6-alkoxy,

C

1

-C

6 -alkoxy substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, methoxymethoxy, amino, C1-

C

3 -alkyl-amino, or (C1-C 3 -alkyl)2-amino, acylamino; in addition, any one substitutent may be an aryl, heteroary, or heterocycloalkyl group.

The term "substituted heteroaryl" as used herein refers to a heteroaryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C 1 -C3-alkyl, C 1

-C

6 -alkoxy, C 1

-C

6 -alkoxy substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, methoxymethoxy, amino, C 1

-C

3 -alkyl-amino, or (C1-C 3 -alkyl)2-amino, acylamino; in addition, any one substitutent may be an aryl, heteroary, or heterocycloalkyl group.

The term "substituted heterocycloalkyl" as used herein, refers to a heterocycloalkyl group, as defined above, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C 1

-C

3 -alkyl, C 1 -C6-alkoxy,

C

1

-C

6 alkoxy substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, methoxymethoxy, amino, C 1

-C

3 -alkyl-amino, or (C1-C 3 -alkyl)2-amino, acylamino; in addition, any one substitutent may be an aryl, heteroary, or heterocycloalkyl group.

Numerous asymmetric centers may exist in the compounds of the present invention.

Except where otherwise noted, the present invention contemplates the various stereoisomers and mixtures thereof. Accordingly, whenever a bond is represented by a wavy line, it is intended that a mixture of stereo-orientations or an individual isomer of assigned or unassigned orientation may be present.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the -69- WO 97/42206 PCT/US97/07702 tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in L haaceuta Sciences. 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptalble salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

As used herein, the term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters includes formates, acetates, propionates, butyates, acrylates and ethylsuccinates.

The term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic WO 97/42206 PCT/US97/07702 forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T.

Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.

Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminun hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgement of the formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants -71- WO 97/42206 PCT/US97/07702 such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility.

The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, Sand granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium -72- WO 97/42206 PCT/US97/07702 phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, -73- WO 97/42206 PCT/US97/07702 inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

According to the methods of treatment of the present invention, bacterial infections are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result. By a "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

The total daily dose of the compounds of this invention administered to a human or other mammal in single or in divided doses can be in amounts, for example, from 0.01 to mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose -74- WO 97/42206 PCT/US97/07702 compositions may contain such amounts or submultiples thereof to make up the daily dose.

In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.

Abbreviations Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: AIBN for azobisisobutyronitrile; Bu3SnH for tributyltin hydride; CDI for carbonyldiimidazole; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DEAD for diethylazodicarboxylate; DMF for dimethylformamide; DMSO for dimethylsulfoxide;

DPPA

for diphenylphosphoryl azide; Et 3 N for triethylamine; EtOAc for ethyl acetate; Et2O for diethyl ether; EtOH for ethanol; HOAc for acetic acid; MeOH for methanol; NaN(TMS)2 for sodium bis(trimethylsilyl)amide; NMMO for N-methylmorpholine N-oxide; TEA for triethylamine; THF for tetrahydrofuran; and TPP for triphenylphosphine.

Synthetic Methods The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes I-VI (to be found following the text describing the schemes) which illustrate the methods by which the compounds of the invention may be prepared. The groups A, B, D, E, W, X, Y, Z, R, R a Rb, Rc, Rd, Re, Rf, Rg and Rh are as defined above unless otherwise noted below.

Scheme I illustrates the preparation of the starting material derived from erythromycin A, a compound of formula (XII). The preparation of protected erythromycin A is described in the following United States patents, US 4,990,602; US 4,331,803,

US

4,680,368, and US 4,670,549 which are incorporated by reference. Also incorporated by reference is European Patent Application EP 260,938. In general, the 9-ketone of compound 1 is protected, for example as an oxime (V is =N-O-OR 1 or =N-O-C(R9)(R10)-O-R' where R 1 R9 and R 1 0 are as defined above), and then either as a separate step or in the same pot, the and 4"-hydroxyls are protected.

The 9-ketone of compound is protected to give compound where V is =N-O-

R

1 where R 1 is as defined above or =N-0-C(R9)(R10)-0-R 1 where R 1

R

9 and R 10 are as defined above. In a preferred embodiment of the process, V is O-(1-isopropoxycyclohexyl) oxime.

The and 4"-hydroxy groups of erythromycin A are protected by reaction with a suitable hydroxy protecting reagent, such as those described by T.W.Greene and P.G.M.

Wuts in Protective Groups in Organic Synthesis, 2nd ed., John Wiley Son, Inc., 1991, which is incorporated by reference, for example, acetic anhydride, benzoic anhydride, WO 97/42206 PCT1US97/07702 benzyl chloroformate or a trialkylsilyl chloride in an aprotic solvent. Examples of aprotic solvents are dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone, dimethylsulfoxide, diethylsulfoxide, N,N-dimethylformamide,

NN-

dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2dimethoxyethane, acetonitrile, ethyl acetate, acetone and the like. Aprotic solvents do not adversely affect the reaction, and are preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof. Protection of and 4"-hydroxy groups of erythromycin A thus affords compound where RP is a hydroxy protecting group. In a preferred embodiment of the process, RP is trimethylsilyl.

Scheme II illustrates the general preparation of the compounds of the invention derived from erythromycin A. The alkylation of the 6-hydroxy group of compound can be carried out with an alkylating agent in a solvent in the presence of a base at a temperature from about -15 0 C to about 50 "C to give compound Alkylating agents include alkyl chlorides, bromides, iodides or alkyl sulfonates. Specific examples of alkylating agents include allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, 4nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, a-bromo-ptolunitrile, cinnamyl bromide, methyl 4-bromocrotonate, crotyl bromide, I -bromo-2pentene, 3-bromo- I1-propenyl phenyl sulfone, 3-bromo- 1 -trimethylsilyl- 1-propyne, 3broino-2-octyne, 1-bromo-2-butyne, 2-picolyl chloride, 3-picolyl chloride, 4-picolyl chloride, 4-bromomethyl quinoline, bromoacetonitrile, epichlorohydrin, bromofluoromethane, bromonitromethane, methyl bromoacetate, methoxymethyl chloride, bromoacetamide, 2-bromoacetophenone, 1-bromo-2-butanone, bromo chloromethane, bromomethyl phenyl sulfone, 1,3-dibromo-l-propene, and the like. Examples of alkyl sulfonates are: allyl O-tosylate, 3-phenylpropyl-O-trifluoromethane sulfonate, n-butyl -0methanesulfonate and the like. It is sufficient to use 1 to 4 mole equivalents of alkylating agents relative to compound Examples of the solvents used are aprotic solvents such as dimethylsulfoxide, diethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide,

N-

methyl-2-pyrrolidone, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone and the like. Examples of the base which can be used include potassium hydroxide, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride, potassium hydride, potassium isopropoxide, potassium tert-butoxide, potassium isobutoxide and the like. The amount of base used is usually 1 to 4 equivalents relative to compound (3.

The deprotection of the and 4'-hydroxyl groups is carried out according to methods described in literature, for example, by T.W.Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 2nd ed., John Wiley Son, Inc., 1991, which is -76- WO 97/42206 PCT/US97/07702 incorporated herein by reference. The conditions used for the deprotection of the and 4'hydroxyl groups usually results in the conversion of X to =N-OH. (For example, using acetic acid in acetonitrile and water results in the deprotection of the and 4'-hydroxyl groups and the conversion of X from =N-O-OR 1 or =N-O-C(R9)(R10)-O-R 1 where R 1

R

9 and R 10 are as defined above to If this is not the case, the conversion is carried out in a separate step.

The deoximation reaction can be carried out according to the methods described in the literature, for example by Greene and Wuts (op. cit.) and others. Examples of the deoximating agent are inorganic sulfur oxide compounds such as sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, sodium dithionate, potassium thiosulfate, potassium metabisulfite and the like. Deoximation may also be accomplished by treatment with an inorganic nitrite salt, for example sodium nitrite or potassium nitrite, in the presence of acid.

Examples of the solvents used are protic solvents such as water, methanol, ethanol, propanol, isopropanol, trimethylsilanol or a mixture of one or more of the mentioned solvents and the like. The deoximation reaction is more conveniently carried out in the presence of an organic acid such as formic acid, acetic acid and trifluoroacetic acid, but may be accomplished with hydrochloric acid also. The amount of acid used is from about 1 to about 10 equivalents of the amount of compound 5 used. In a preferred embodiment, the deoximination is carried out using an organic acid such as formic acid in ethanol and water to give the desired product (6t).

The desired 6-O-"alkylated" compound may be prepared directly as described above or obtained from chemical modification of an initially prepared 6-O-"alkylated" compound.

Representative examples of further elaboration of the 6-position are shown in Scheme m and Scheme IV. For example, compound (6AI, which is a compound of formula (6) wherein R is -CH 2 CH=CH2 (prepared with allyl bromide as the alkylating reagent) and wherein M represents the macrolide ring system, can be further derivatized. The double bond of the allyl compound can be reduced to give the 6-O-propyl compound (b) treated with osmium tetroxide to give the 2,3-dihydroxypropyl compound oxidized with 3-chloroperoxybenzoic acid to give the epoxy methyl compound which can be opened with nucleophiles such as amines or N-containing heterocyclic compounds, for example, to give compounds with N-containing side chains oxidized under Wacker conditions Tsuji, in "Organic Synthesis with Palladium Compounds", NY, Springer- Verlan, 1980, pp. 6-12) to give the 6-O-CH 2 -C(O)-CH3 compound brominated with hydrogen bromide perbromide to give (121; reacted with aryl halides under Heck conditions Heck, Org. React., 1982, 22,345-390.) to give oxidized with ozone to give the 6-O-CH 2 -CHO compound (14) which can in turn be converted to -77- WO 97/42206 PCT/US97/07702 oxime (M by reaction with H 2 NOR', (ii) converted to hydrazone (51 by reaction with

H

2 NNR'R", and (iii) reductively aminated with primary amines, H 2 NR', in the presence of NaCNBH3 to give Reaction of oxime where with diisopropylcarbodiimide in the presence of CuCl gives nitrile (1 In Scheme IV, the propargylic compound (12 which is a compound of formula (6) of Scheme II wherein R is CH 2 CCH (prepared with propargyl bromide as the alkylating reagent) can also be further derivatized. The triple bond can be coupled to aryl halides using Pd (II) or Pd(0) catalysts in amine solvents in the presence of co-catalytic CuI (Sonogashira et al., Tetrahedron Lett., 1975, 5Q, 4467-4470.) to give the aryl substituted alkyne compound (2Qh brominated with N-bromosuccinimide in the presence of silver nitrate (Weichert, Angew. Chem. Int. Ed. Engl., 1984, 23, 727-728) to provide the brominated alkyne (25; hydroborated with 9-BBN to give the boronated compound which is then treated with an aryl or alkenyl halide or sulfonate in the presence of Pd(0) catalysts according to the method of Suzuki (Pure Appl. Chem., 1985, 52, 1749-1758) to give the aryl sustituted olefin or a conjugated diene compound coupled to terminal alkynes in the presence of cupric salts under conditions of the Eglinton Reaction (Eglinton and McCrae, Adv. Org. Chem. 4, 225-328, 1963.) to generate diynes or coupled with acyl halides utilizing cocatalytic Pd(II)/Cu(I) in amine solvents (Sonogashira, Hagihara, N.; Tohda, Y. Synthesis, 1977, 777-778.) to give the alkynyl ketone Compound (20) can be selectively reduced to the corresponding cis olefin (21) by catalytic hydrogenation in EtOH at atmospheric pressure in the presence of 5% Pd/BaSO4 and quinoline.

Scheme V illustrates the preparation of compounds of formulae IV, V, VI, and VII of the invention. Compounds (from Scheme II) are protected at the 2' and 4" hydroxy positions to give compounds Compound 26 may be treated with formaldehyde in the presence of an acid, or with chloroiodomethane in the presence of base (according to the procedure of Hunt et al., J. Antibiotics, (1988), 41: 1644) to give the protected 11,12methylenedioxy compound of formula (IV which may optionally then be deprotected at the 2' and 4" positions by methods described above to give a 11,12-methylenedioxy compound of formula (IV}.

To prepare compound (21) the compound (26) is reacted is reacted under anhydrous conditions with base such as sodium hydride, lithium hydride, potassium carbonate or dimethylaminopyridine and followed by phosgene, diphosgene, triphosgene or benzyl chloroformate in an aprotic solvent, as defined above. The reaction may require cooling or heating, depending upon the conditions used. The reaction temperature may be from -20 °C to 70 and preferably from 0 OC to room temperature. The reaction may require hours to 10 days, and preferably 1-5 days, to complete. Compound (22) may optionally -78- WO 97/42206 PCT/US97/07702 then be deprotected at the 2' and 4" positions by methods described above to give the 11,12carbonate compound of formula Intermediate compound (2 8may be prepared from compound by treatment of the latter with under anhydrous conditions with NaH and CDI in an aprotic solvent, preferably THF, DMF or a mixture thereof. The reaction may require cooling or heating, depending upon the conditions used. The reaction temperature may be from -20 OC to and preferably from 0 °C to room temperature. The reaction may require 0.5 hours to 10 days, and preferably 1-5 days, to complete.

Alternately, compound (2B) may be prepared directly from compound (26) by reaction with sodium hydride or lithium hydride and CDI under anhydrous conditions in an aprotic solvent, as defined above, which does not adversely affect the reaction, preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof. The resulting alkoxide is then reacted with excess carbonyldiimidazole for hours to 10 days in the same reaction mixture to produce The preferred temperature is from -10 oC to ambient.

Hydrolysis of compound (28 gives the 10,11-anhydro compound of formula (Y.

To prepare compounds (22) which may converted to the unprotected compounds of Formula (VII), a compound (27) may be treated with several different reagents, each chosen to prepare a compound wherein the W group is unique. To prepare a compound (22) wherein W is absent, compound is reacted with a primary amine RNH2 in a suitable solvent at room temperature to reflux temperature for about 4 to about 48 hours. Suitable solvents include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tbutanol, and the like, aprotic solvents such as methylene chloride, tetrahydrofuran,

N-

methyl-pyrrolidinone, diethyl ether, bis-methoxymethyl ether, dimethyl formamide, and acetone, for example, as well as aqueous mixtures thereof. Preferred solvents are aqueous acetonitrile, aqueous DMF, and aqueous acetone.

In the primary amine RgNH 2 and in the resulting compound of Formula (VII), Rg may be hydrogen,

C

1 -C6-alkyl,

C

3

-C

7 -cycloalkyl, aryl, substituted-aryl, heteroaryl or substituted-heteroaryl. When Rg is a C 1

-C

6 -alkyl substituent, the alkyl group may be optionally substituted with one or more substituents such as aryl, substituted-aryl, heteroaryl, substituted-heteroaryl, hydroxy, C 1

-C

6 -alkoxy, NR 9

R

10 wherein R 9 and R 10 are independently selected from hydrogen and C 1 -C6-alkyl, or NR 9

R

10 wherein R 9 and R1 0 are taken with the nitrogen atom to which they are connected to form a 3- to 7membered ring. In the instance wherein the NR 9

R

10 substituent is a 5- to 7-membered ring, the ring may optionally contain a hetero function consisting of -N(CI-C6alkyl-)-, -N(aryl)-, -N(aryl-C 1 -C6-alkyl-)-, -N(substituted-aryl-C1-C 6 -alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C -C6-alkyl-)-, -79- WO 97/42206 PCT/US97/07702 or wherein n is 1 or 2. Additionally, when R8 is C 1 -C6-alkyl it may bear an optional substituent of the formula -CH 2

-M-R

11 wherein M may be

-NH-

wherein n is 0, 1 or 2, -0and and R 11 may be aryl, substituted-aryl, heteroaryl, substitutedheteroaryl, heterocycloalkyl, or a C 1

-C

6 -alkyl optionally bearing one or more substituents such as aryl, substituted-aryl, heteroaryl, or substituted-heteroaryl. Chromatographic treatment of the crude reaction product affords both the natural and epi isomers at position of the molecule.

To prepare a compound wherein W is compound (2a) is reacted with a hydrazine reagent such as unsubstituted hydrazine or a substituted hydrazine in a solvent such as described immediately above to afford the desired compounds of (22) and the deprotected compounds of Formula (VII). The natural and C-10 epimers of these compounds may be isolated from the reaction mixture. Deprotection of the protected hydroxy groups may be accomplished by standard methods as described by Wuts and Greene (op. cit.).

Thus, treatment of compound with unsubstituted hydrazine affords the compounds of (22) and Formula (VII) wherein W is -NH- and Re is H.

Also, treatment of (2a) with a substituted hydrazine RgR 4 NNH2, wherein Rg is as defined above and R 4 is C 1

-C

6 -alkyl, gives the compounds of (22) and Formula (VII) wherein W is -N(C 1

-C

6 -alkyl)-.

Optionally, the compound of Formula (VII) wherein W is -NH- and R9 is H can be treated with an R9 -acyl acylating agent, wherein R9 is as defined above, to afford a compound of Formula (VII) wherein W is -NH-CO-. The acylating agents can he. for example, an acid chloride, an acid fluoride, an acid anhydride, or a carboxylic acid in the presence of a carbodiimide coupling reagent such as carbonyldiimidazole or 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, for example, wherein RP is as defined above.

Optionally, the compound of Formula (VII) wherein W is -NH- and R9 is H can be treated with an aldehyde Rg -CHO, wherein Re is as defined for Formula to afford a compound of Formula (VII) wherein W is -N=CH-.

Optionally, the compounds of Formula (VII) wherein W is -N=CH- can be reduced to yield additional compounds of Formula (VII) above, wherein W is -NH- using reducing reagents such as sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride, borane-tetrahydrofuran complex, and borane-piperidine complex, for example.

Also shown in Scheme V is the procedure by which compounds of (22) and Formula (VII) wherein W is and R is H or O-C 1

-C

6 -alkyl may be prepared. Under 80 WO 97/42206 PCT/US97/07702 reaction conditions similar to those shown above for hydrazine reagents, treatment of compound with unsubstituted hydroxylamine or an O-C 1

-C

6 -alkylated hydroxylamine affords the desired compound.

For example, treatment of compound (28) with an excess of hydroxylamine affords the compounds of (22) and Formula (VII) wherein W is and R is H.

Treatment of compound (28) with an O-C 1

-C

6 -alkylated hydroxylamine affords the desired compounds of (22) and Formula (VII) wherein W is and R is C1-C6-alkyl.

Optionally, it is possible to further treat the compound of Formula (VII) wherein W is and Rg is H with a suitable base and an appropriate electrophile to prepare a compound wherein W is and Rg is C 1 -C6-alkyl, C 3

-C

7 -cycloalkyl, aryl, substitutedaryl, heteroaryl or a substituted-heteroaryl group, wherein these terms are as defined for compounds of Formula (VII) above. The base may be an alkali metal hydride or an organoalkali metal compound, including but not limited to sodium hydride, potassium hydride, lithium hydride, lithium diethylamide, and butyllithium. The electrophile is a compound having the formula R9 wherein Rg is as defined immediately above, and L is halide or another suitable leaving group, such as a methanesulfonyl or p-toluenesulfonyl moiety.

Optional deprotection of any of the compounds wherein W is may be accomplished by standard methods as described by Wuts and Greene (op. cit.).

As outlined in Scheme VI, compounds of Formulas (VII) and (IX) may be synthesized. Thus, a starting material compound of formula obtained according to Scheme V, is reacted with a 1,2-diamine compound having the formula: NH2 B" NH 2 wherein A, B, D, and E are as defined above, in a suitable solvent at room temperature to reflux temperature for about 4 to about 48 hours to give the bicyclic compound of formula The 1,2-diamine compound may have the substituents A, B, D and E, as defined above for the compounds of Formula (VIII), but with C2 or Cs symmetry or A=B=H.

Suitable solvents include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like, aprotic solvents such as methylene chloride, tetrahydrofuran, N-methyl-pyrrolidinone, diethyl ether, bis-methoxymethyl ether, dimethyl formamide, and acetone, for example, as well as aqueous mixtures thereof. Preferred solvents are aqueous acetonitrile, aqueous DMF, and aqueous acetone.

Optionally, the 2'-and 4"-hydroxy protecting groups on compound (22) may removed by standard methods as described by Wuts and Greene (op. cit.). When OR f is an -81- WO 97/42206 PCT/US97/07702 ester, for example, such as acetate or benzoate, the compound is preferably deprotected by treatment with methanol or ethanol. When Rf is a trialkylsilyl group, the compound may be deprotected by treatment with fluoride in THF or acetonitrile. The reaction time required may be from about 1 to about 24 hours.

The deprotected compound (22) wherein R f is H is then cyclized to give compounds (3Q) by treatment with a dilute concentration of a strong acid at ambient temperature to reflux temperature for about 4 hours to about 10 days in a suitable organic solvent. Suitable acids include, but are not limited to, hydrochloric acid, sulfuric acid, dichloroacetic acid, trichloroacetic acid and the like. The reaction may be accomplished with a suspension of the reagents in aqueous alcohol, such as for example, methanol, ethanol, propanol, isopropanol, butanol, iso-butanol and t-butanol, for example.

Optionally, compound (22) may be deprotected by the standard methods as described by Wuts and Greene (op. cit.) to give compounds of Formula (VIII). In the event that the protecting groups were removed before the cyclization step, then compound represents compounds of Formula (VIII).

The compounds having Formula (VIII) may be converted into compounds having Formula (IX) Macrolides of the Formula (VIff) may be converted into compounds having Formula (IX) by treatment with reducing agents such as sodium cyanoborohydride at pH 4-5 or sodium borohydride in a suitable organic solvent.

Scheme VI also illustrates an alternate preparation for compounds of Formulas (VIII) and Starting material is reacted with a compound having the formula: B NH 2 wherein A, B, D, and E are as defined above, in a suitable solvent at 0 70 °C for about 4 to about 48 hours to give compound Suitable solvents are those such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, methylene chloride, tetrahydrofuran,

N-

methyl-pyrrolidinone, diethyl ether, bis-methoxymethyl ether, dimethyl formamide, acetone, aqueous acetonitrile, aqueous DMF, and aqueous acetone, for example.

Compound (31) is then treated with triphenylphosphine and diphenylphosphoryl azide-DEAD in tetrahydrofuran under Mitsunobu reaction conditions to give the compound (32) wherein Y=N3. Compound (32) wherein Y=N3 is then deprotected by standard methods as described above.

-82- WO 97/42206 PCT/US97/07702 Compound (32) wherein Y=N 3 is then reduced to the amino compound (32A) wherein Y=NH2 (not shown). Preferable reducing reagents are triphenylphosphine-water, hydrogen with a catalyst, sodium borohydride, or dialkylaluminum hydride.

Compound (32A) wherein Y=NH2 is then cyclized to prepare the compounds (3Q) and Formula (VIII) by treatment with a dilute concentration of a strong acid at ambient temperature to reflux temperature for about 4 hours to about 10 days in a suitable organic solvent. Suitable acids include, but are not limited to, hydrochloric acid, sulfuric acid, dichloroacetic acid, trichloroacetic acid and the like. The reaction may be accomplished with a suspension of the reagents in aqueous alcohol, such as for example, methanol, ethanol, propanol, iso-propanol, butanol, iso-butanol and t-butanol, for example. This treatment also removes protecting groups at positions R 1 and R 2 which eliminates the need to isolate and treat compound (3Q) separately.

In an another alternate series of reactions the hydroxy group (derived from the amino alcohol) in compound (31) may be activated by treatment with a sulfonating agent, such as sulfonyl chloride, alkyl or aryl sulfonic anhydride or trifluoromethanesufonic anhydride, in an aprotic solvent diethyl ether, dichloromethane, tetrahydrofuran, chloroform, pyridine or a mixture thereof) to give the compound (32) wherein Y is a sulfonate ester. The reaction requires cooling or heating, depending on the conditions used.

The reaction temperature is preferably -100 0 C to 10 The reaction may require minutes to 24 hours to complete. The sulfonate ester activated hydroxy group in (32) (for example, Y=-OSO 2 CF3) is then converted to an azide to give the second intermediate azide compound (32A, not shown) wherein Y=N3 by reacting with an alkali metal azide, such as lithium azide or sodium azide, in the same solvent defined above. The reaction temperature is preferably about 0 0 C to about 100 0 C. The azido compound is then converted to compounds (30) and Formulas (VII) and (XI) according to the procedures described above.

It is understood that the foregoing chemistry is merely illustrative and is not to be taken as a limitation upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and may be made without departing from the spirit and scope thereof. Thus, while the foregoing chemistry is directed primarily to the preparation of compounds of formula II, the analogous compounds of formulae III, IV, V, VI, VII, VIII, and IX can be prepared in like manner.

Compounds of formula III wherein R is hydrogen, are described in United States patents US 5,075,289 and US 5,217,960 which are incorporated herein by reference.

Chemistry relating to these macrolides is also described by Kirst et al. in J. Med. Chem., 33: 3086 (1990) which is also incorporated herein by reference. Compounds of formula IV wherein R is hydrogen are described by Hunt et al. in J. Antibiotics, 41: 1644 (1989), -83 WO 97/42206 PCT/US97/07702 which is incorporated herein by reference. Compounds of formula V, VI and VII wherein R is hydrogen are described by Baker et al. in J. Org. Chem., 53: 2340 (1988), which is incorporated herein by reference. Compounds of formula VIII and IX wherein R is hydrogen are described in European Patent Application EP 559,896, which is incorporated herein by reference.

Scheme I H NMe 2 H H NMe 2 OH O O,, HO, 6 HO,, 6 O HO HO o 0o 0 H 0 O- H OMe OMe -84- PCTIUS97/07702 WO 97/42206 Scheme 11 R Hj NMe 2 I 00

H

PCT[US97/07702 WO 97/42206 0 Scheme III 13 OH R' M -0 9 0 M 0 OH 3 Br J22

O

.M-0

CH

3 M-0 7

R

AN- 0 M-0 17

H

M0 0

H

N- R' M-0

N--N

f-- 86 PCTIUS97/07702 WO 97/42206 0 Scheme IV

I'

.rA' is aryl or )conjugated alkenryl Ar M -0 M -o -Ar M -0 19 Ar M-0 0 24 87 PCTfUS97/07702 WO 97/42206 Scheme V 6protect

IV

88 PCT/US97/07702 WO 97/42206 Scheme VI

D

A NH

NH

2 2 steps

VIII

IX

ilx The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.

-89- PCT/US97/07702 WO 97/42206 0 Example 1 Compound of Formula X is R is allyl Example 1A Compound of Formula (XII): X is =N-O-(l-isopropoxycyclohexvl). R is allyl.

pBE is Trimethylsilvl To a 0 OC solution of 5 g of the compound of Formula XII where X is =N-O-(1-isopropoxycyclohexyl) and RP is trimethylsilyl in 15 mL of DMSO and 20 mL of THF was added 1.23 mL of freshly distilled allyl bromide. After approximately minutes, a solution prepared by warming and stirring (556 mg, 2.05 equivalents) of powdered KOH in 25 mL of 1:1 THF-DMSO at 50 °C for 20-30 minutes was added dropwise over 5 minutes. After about 1 hour, the chilled reaction mixture was treated with 200 mL of EtOAc followed by 762 iL of allyl amine followed by 60 mL of water. The organic layer was washed with water followed by brine, dried over MgSO4, filtered and concentrated in vacuo to afford 5.3 g of crude title compound. Purification by silica gel chromatography eluting with 5% acetone in hexanes containing 0.25% triethylamine afforded 2.35 g of the title compound.

Example 1B Alternate preparation of Compound of Formula (XII): X is -isopropoxycyclohexyl). R is allyl.

RD is Trimethvlsilvl To a solution of 103.2 g (0.100 mmol) of the compound of Formula XII where X is =N-O-(1-isopropoxycyclohexyl) and RP is trimethylsilyl in 500 mL of DMSO and 500 mL of THF cooled to 0 °C and flushed with nitrogen was added freshly distilled allyl bromide (17.3 mL) over 10 minutes. A solution of potassium t-butoxide (120 mL 1M THF solution, 0.120 mmol) in THF (100 mL) and DMSO (230 mL) was added dropwise over 3.5 hours at 0 oC, and the mixture was stirred at 0 °C under nitrogen for 2 hours. Additional potassium t-butoxide solution was added (50 mL 1M THF solution, 0.05 mmol, in 50 mL of DMSO) dropwise over 1 hour, and the mixture was stirred for 2 hours. The mixture was cooled and taken up in ethyl acetate (1.5 This solution was washed with water and brine, then dried over Na2SO4. Removal of the solvent under vacuum gave the title compound (125.1 g).

Example 1C Compound of Formula X is =N-OH, R is allyl To a solution of the compound resulting from Example 1A (1.7 g) in 17 mL of acetonitrile and 8.5 mL of water was added 9 mL of HOAc at ambient temperature. After WO 97/42206 PCT/US97/07702 several hours at ambient temperature, the reaction mixture was diluted with 200 mL of toluene and concentrated in vacuo. The residue obtained was found to contain unreacted starting material, so additional acetonitrile (15 mL), water (70 mL) and HOAc (2 mL) was added. After 2 hours, an additional 1 mL of HOAc was added. After approximately three more hours, the reaction mixture was placed in the freezer overnight. The reaction mixture was allowed to warm to ambient temperature, diluted with 200 mL of toluene and concentrated in vacuo. The residue was chased two times with toluene and dried to constant weight (1.524 g).

Example ID Compound of Formula X is R is allyl The compound resulting from Example 1C (1.225 g) in 16 mL of 1:1 EtOH-water was treated with NaHSO3 (700 mg) and formic acid (141 gIL) and warmed at 86 °C for hours. After approximately three hours, the reaction mixture was allowed to cool to ambient temperature, diluted with 5-6 mL of water, basified with 1 N NaOH to pH 9-10 and extracted with EtOAc. The combined organic extracts were washed with brine dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography eluting with 1% MeOH in dichloromethane containing 1% ammonium hydroxide to give 686 mg of the title compound. 13 C NMR (CDC13) 8 219.3 174.8 135.5, 116.3, 101.9 95.9 79.7 78.8 (C- 78.5 74.1 72.4 70.6 68.1 65.5 (allylic methylene), 65.1 49.0 O-CH3), 45.0 44.1 39.7 (NMe2), 37.9 37.1 34.6 28.4 21.0, 20.6 CH3, C-6' CH3), 20.8 (C- 14), 18.3 18.1 (C-8 CH 3 15.7, 15.6 (C-2 CH 3 C-6 CH 3 11.9 (C-10 CH3), 10.1 8.9 (C-4 CH 3 MS (FAB)+ m/e 774 812 Example

IE

Alternate preparation of Compound of Formula X is R is allyl A sample of the compound prepared according to Example 1B (76.2 g) was dissolved in H20 (120 mL) and EtOH (120 mL), then pellets of NaNO2 (33.5 g, 0.485 mol, 5 equiv) were added to the solution and the reaction mixture was stirred until the NaNO2 was dissolved. Hydrochloric acid (4N, 121 mL, 0.484 mol) was then added dropwise over a 10 minutes with rapid stirring. The reaction mixture was then heated to OC and stirred for 2 hours. The reaction mixture was cooled, and solid NaHCO3 was added slowly until the solution was saturated. The mixture was then concentrated to approximately half its volume under reduced pressure and extracted with ethyl acetate (3 x).

The organic extract was washed with brine and dried with Na2SO4. The solvent was -91- 0 WO 97/42206 PCT/US97/07702 removed under reduced pressure, and the residue was crystallized from acetonitrile to give 29.2 g of desired product. A second crop of crystals gave an additional 7.02 g of material.

Analytical data was as in Example 1D above.

Example 2 Compound of Formula X is R is propyl The compound resulting from Example 1 (100 mg) was catalytically hydrogenated in MeOH (10 mL) using a palladium on carbon catalyst and hydrogen. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The crude product (93 mg) was purified by column chromatography on silica gel eluting with 1% MeOH in dichloromethane containing 1% ammonium hydroxide to afford 38 mg of the title compound. 13 C NMR (CDC13) 8 220.5 175.1 102.2 96.4 79.8 (C-5),79.0 78.7 77.8 76.4 74.4 72.8 71.1 68.8, 68.5, 66.0, 65.9, 65.6, 49.4 -OMe), 45.3 44.5, 40.2 (-NMe2), 38.4 38.2 37.4 35.1, 28.6, 21.8, 21.5 21.3, 21.0 Me, 6 Me), (18.7, 18.6 Me, 8 (16.2, 16.1 (C-2 Me, 6 12.3 Me), 10.5 10.1, 9.4 (C-4 Me). MS (DCI/NH3) m/z 776 (M+H) Example 3 Compound of Formula X is R is 2.3-dihydroxypropyl To an ambient temperature solution of the compound resulting from Example 1 (100 mg) in 6 mL of THF was added N-methylmorpholine N-oxide (98 mg) followed by 32 pIL of 4% by weight osmium tetroxide in water. The reaction mixture was stirred overnight and then quenched by the addition of 3 equivalents of NaHSO3. After stirring at ambient temperature for 10 minutes, the reaction mixture was filtered through a silica gel plug eluting with 5% MeOH in dichloromethane containing 1% ammonium hydroxide to afford, after concentration at reduced pressure, the title compound (81 mg, 77%) as a mixture of epimers. 13 C NMR (CDC13) 5 222.6, 221.6 176.9, 176.0 102.2 102.1, 96.5 96.4, 80.0, 79.9, 79.8, 78.8, 78.7, 77.6, 77.5, 77.2, 77.0, 76.7, 74.8, 74.7 72.8 71.0, 71.0, 70.9 70.9, 68.9, 68.9, 68.5, 66.8, 66.5, 66.3, 66.2, 65.8, 65.6, 63.3, 63.0 55.3, 49.3 (-OCH 3 45.6, 45.4 44.7 40.2 (-NMe2), 38.4, 38.2, 38.2, 37.9, 37.6, 35.1 35.0, 28.5, 28.5 21.7, 21.5, 21.5, 21.4, 21.0, 20.9, 18.8, 18.6, 18.5, 16.2, 16.2, 16.0, 11.9 (C- CH3), 10.4 10.4, 9.4 (C-4 CH3), 9.3. MS m/z 808 -92- WO 97/42206 PCT/US97/07702 Example 4 Compound of Formula X is R is 2.3-epoxypropyl To an ambient temperature solution of the compound resulting from Example 1 (100 mg) in 1.5 mL of dichloromethane was added -170 mg of m-chloroperoxybenzoic acid.

The reaction mixture was stirred at ambient temperature overnight and concentrated in vacuo. The residue obtained was taken up in EtOAc and washed with saturated sodium bicarbonate solution (2x) followed by brine, dried over MgSO4 and concentrated in vacuo to afford 93 mg of crude product. The crude product was redissolved in EtOAc and washed with 1 M NaHSO3 followed by NaHC03 solution and brine, dried over MgSO4 and concentrated in vacuo. The residue obtained was chromatographed on silica gel eluting with MeOH in dichloromethane containing 1% NH 4 0H to afford the title compound as a mixture of epimers. 13 C NMR (CDC13) 8 219.8, 219.0 175.5, 175.2 102.2, 102.2 96.3, 96.2 80.2, 79.9, 79.6, 79.0, 78.8, 77.8, 77.7, 76.6 (C- 74.6 72.7 71.0 68.8, 68.8, 68.5 (66.2, 66.0 (66.1, 65.6 50.3, 49.8, 49.3 OMe), 46.6, 45.5, (45.3, 45.2 44.6, 44.6 40.2 (-NMe2), 38.4 38.2, 38.2, (37.6, 37.5 35.1 35.0, 28.8 (21.4, 21.2, 21.1, 20.9 Me, 6' Me, C-14), (18.7, 18.6, 18.5 Me, 8 (16.1, 16.0, 15.9 (C-2 Me, 6 12.2 (C-10 Me), 12.2, 10.5 9.3 (C-4 Me), 9.2. MS (FAB) m/e 790 (M+H) 812 (M+Na) 828 (M+K) High Resolution Mass Spec m/z Calcd for C 4 0H 7 1NO14K: 828.4512. Found: 828.4516.

Example Compound of Formula X is R is 2-hydroxy-3-(imidazol-1-vl)propyl To an ambient temperature solution of the compound resulting from Example 4 (100 mg) in -1 mL of chloroform was added 17 mg of imidazole. The reaction vessel was sealed and stirring was continued at ambient temperature for 1 hour. Two additional equivalents of imidazole were added, and stirring was continued for several days. The solvent was removed under reduced pressure, and the crude material obtained was purified by column chromatography eluting with 5% MeOH in dichloromethane containing 1% NH40H to afford 44 mg of the title compound. 1 C NMR (CDC13) mixture of epimers 8 223.3, 221.2 176.4, 175.9 137.9, 128.7, 120.1, 119.9, 102.2, 102.1 96.5 80.3, 80.0, 79.7, 79.2, 78.9, 77.6, 77.6, 77.4, 77.2, 77.0, 77.0, 76.7, 74.7, 74.6, 72.7, 72.7, 71.0, 69.7, 69.4, 69.0, 69.0, 68.5, 68.5, 66.8 66.0, 65.5, 65.4, 50.2, 49.3 49.3 -OMe), 45.5 45.2 44.7 40.1 (-NMe2), 38.2 38.1 37.8, 37.5, 35.0, 34.9 28.4 21.6, 21.4, 21.3, 21.3, 21.2, 20.9, 20.8, 18.9, 18.8, 18.7, 18.6, 16.2, 16.1 16.0 (C-2 Me, C-6 Me), -93- WO 97/42206 PCT/US97/07702 11.9 (C-10 Me), 10.4 9.3 (C-4 Me). MS m/z 858 High Resolution Mass Spec m/z Calcd for C4 3 H76N3014: 858.5327. Found: 858.5320.

Example 6 Compound of Formula X is R is 2-hvdroxv-3-(morpholin- 4 -vl)propvl To an ambient temperature solution of the compound resulting from Example 4 (100 mg) in 1 mL of chloroform was added 22 tL of morpholine. The reaction vessel was sealed and stirring was continued at ambient temperature for 1 hour. Two additional equivalents of morpholine was added and stirring was continued for several days. The solvent was removed under reduced pressure, and the crude material obtained was chromatographed on silica gel eluting with 3% MeOH in dichloromethane containing 1%

NH

4 0H to give 35 mg of the title compound. 13 C NMR (CDC13) mixture of epimers 8 220.3, 219.1 176.1, 175.5 102.1, 102.1 96.2, 96.1 (C- 80.0, 79.8, 79.7, 79.1, 78.6, 78.5, 77.8, 77.7, 77.1, 76.6, 75.0, 75.0, 72.8, 71.0, 68.5, 68.2, 67.8, 67.0, 66.9, 66.4, 66.0, 65.9, 65.5, 65.5, 61.4, 60.8, 53.9, 53.8, 49.3, 49.3 45.5, 45.4 44.8, 44.7 40.2 (-NMe2), 38.3 38.2, 38.1, 37.9, 37.7 35.0, 28.5 21.7, 21.5, 21.4, 21.4, 21.3, 21.3 (C-14, 3"- Me, 21.1, 19.0, 18.7, 18.6, (C-8 Me, C-6" Me), 16.3, 16.2, 16.0 (C-2 Me, 6 Me), 12.1, 12.0 (C-10 Me), 10.6, 10.5 9.3 (C-4 Me). MS (FAB) m/e 877 (M+H) 915 (M+K) Example 7 Compound of Formula X is R is 2-hvdroxv-3-(benzvlamino)propvl To an ambient temperature solution of the compound resulting from Example 4 (140 mg) in 1.5 mL of chloroform was added 3 equivalents (58 gL) of benzylamine. The reaction mixture was stirred overnight at ambient temperature and then warmed at 62 °C for approximately 3 hours and then stirred overnight at ambient temperature. The reaction mixture was then heated at 70 °C for 2 hours and then concentrated in vacuo. The residue was chased two times with toluene to afford 170 mg of crude title compound. Crude product was purified by silica gel chromatography eluting with 2% MeOH in dichloromethane containing 1% NH40H to give the title compound as a mixture of epimers.

13 C NMR (CDC13) 8 221.7, 220.1 176.4 175.7, 140.7, 128.5, 128.2, 128.1, 128.1, 126.7, 126.6, 126.5, 102.2 96.2 79.6, 79.3, 78.8, 78.7, 77.6, 77.6, 76.8, 76.7, 74.9, 72.7, 72.7, 71.0, 69.7, 69.1, 68.7, 68.5, 67.9, 67.8 (C- 16), 66.0, 65.6, 53.8, 53.6, 51.6, 51.3, 49.3 (-OCH 3 45.5 45.4, 44.7, 44.6 (C- 40.2 (-NMe2), 38.2, 38.2 38.0, 37.9 (C-10, 35.0, 34.8 28.5 -94- WO 97/42206 PCT/US97/07702 21.7, 21.4, 21.4, 21.1, 21.1, 18.9, 18.6, 18.6, 16.2, 16.2, 16.0, 15.9, 12.1, 12.0 CH3), 10.5 9.3, 9.3 (C-4 CH 3 MS m/z 897 (M+H) Example 8 Compound of Formula X is R is 2-oxoethyl Method A. To a solution of the compound from Example 3 (275 mg) in 6.5 mL of a aqueous THFwas added 87 mg of NaIO4. The reaction was stirred at ambient temperature for 2 hours and then 0.5 equivalents of NaIO4 was added. After 2 additional hours, another 0.5 equivalent of NaIO4 was added. After two more hours, the reaction mixture was filtered through a silica gel plug eluting with 4% MeOH in dichloromethane containing 1% NH 4 0H to afford 195 mg of the title compound. 13 C NMR (CDC13) 8 221.0 203.2 (CHO), 175.5 102.4 96.3 80.5, 79.8, 78.8, 77.7, 76.7, 74.5 72.7 71.0, 70.3, 68.9, 68.7, 66.1, 65.6, 49.4 (C-3" OMe), 45.3, 44.7, 40.2 (NMe2), 38.4 38.2 37.4 34.9 28.5 (21.5, 21.4, 21.1 Me, 6 21.0, (18.8, 18.5 (C-8 Me, 6" 16.0 (C- 2 Me), 12.2 (C-10 Me), 10.4 9.2 (C-4 Me). Mass Spec m/z 776 Method B. A solution of the compound from Example 3 (8 g) in 350 dichloromethane (8 mL) was cooled to -78°C, ozone was bubbled into it until a blue color persisted, and nitrogen was then bubbled through it until the blue color disappeared. Methyl sulfide (6 mL) was added, the solution was warmed to 0 OC and stirred for 30 minutes. The solvent was removed under vacuum, the residue was redissolved in THF (90 mL). and triphenylphosphine (7.5 g) was added. The mixture was stirred at 55 OC for 4.5 hours.

then concentrated in vacuo and dried under high vacuum to give the crude product (16.5 g) Flash chromatography on silica gel (10:1) eluting with acetone/hexanes/triethylamine (75:25:0.35) gave of the title compound (4.9 g, Mass Spec m/z 776 Example 9 Compound of Formula X is R is 2-oxopropyl A mixture of 1.5 mL of 7:1 DMF-H20, 5 mg PdC12 and 21 mg of CuCl was stirred under an oxygen atmosphere for -1.33 hours. To this mixture was added a solution of the compound resulting from Example 1 (150 mg) in 1.5 mL of 7:1 DMF-H20 dropwise over minutes. The reaction mixture was warmed to 50 OC and maintained at that temperature for approximately 1 hour and at ambient temperature overnight. Additional portions of PdC1 2 (5 mg) and CuCl (21 mg) were added. The reaction mixture was warmed to 54 °C and maintained at that temperature for about 3 hours. The reaction mixture was allowed to WO 97/42206 PCT/US97/07702 cool to ambient temperature and then 02 was bubbled through the reaction mixture which was stirred overnight at ambient temperature. Additional PdC12 (10 mg) and CuCl (42 mg) were added, and the 02 was continued. The reaction mixture was warmed to 40 °C for about 3 hours and then stirred over the weekend at ambient temperature. The reaction mixture was diluted with EtOAc and washed two times with 30% aqueous ammonium hydroxide solution and two times with brine, dried over MgSO4 and concentrated in vacuo to afford 85 mg of crude title compound. Purification by eluting through a silica gel plug with 1% MeOH in dichloromethane containing 1% ammonium hydroxide afforded 47 mg of the title compound. 13 C NMR (CDC13) 8 217.9, 205.3, 175.0, 102.4, 96.5, 80.6, 79.0, 78.9, 77.7, 76.7, 75.1, 72.7, 71.0, 69.6, 68.7, 68.3, 66.1, 65.6, 49.4, 44.8, 40.2, 38.4, 37.6, 35.0, 28.5, 26.5, 21.4, 21.3, 19.2, 18.7, 16.2, 15.9, 12.2, 10.6, 9.3. High Resolution Mass Spec (FAB) Calcd for m/z

C

40 H72NO12: 790.4953. Found: m/z 790.4932.

Example Compound of Formula X is R is -CH-C=CH Example Compound of Formula X is =N-O-(-isopropoxvcyclohexyl) R is -CH-C=CH A solution of 1.14 g of powdered KOH in 30 mL of anhydrous DMSO and 30 mL of anhydrous freshly distilled THF was added via addition funnel to a 0 oC solution of the compound of Formula XII where X is =N-O-(1-isopropoxycyclohexyl) and RP is trimethylsilyl (10 g) in 60 mL of 1:1 DMSO-THF. This was followed by a solution containing 2.38 mL of propargyl bromide in toluene added over 10-15 minutes. The reaction mixture was stirred at 0 oC for about one hour and then 2 additional equivalents of propargyl bromide was added at 0 OC. After 2 hours, 2 equivalents of powdered KOH (-1 g) was added at 0 OC, and the reaction mixture was placed in the refrigerator overnight. The next day an additional 4 mL of propargyl bromide was added at 0 OC. When tic indicated that the reaction was complete, the reaction was quenched with 10 equivalents of allylamine at 0 °C and stirred for 5 minutes. The mixture was diluted with H20 and EtOAc, and the organic layer was washed with water and brine, then dried over MgSO4 and concentrated under reduced pressure to afford 11.5 g of crude title compound. Filtration through a silica gel plug eluting with 10% acetone in hexane containing 0.25% Et 3 N afforded 9.3 of purified title compound.

96- WO 97/42206 PCT/US97/07702 Example Compound of Formula R is -CH2-C=CH. X is =N-O-H To the compound resulting from Example 10A (9.3 g) in 50 mL of acetonitrile and mL of water was added 50 mL of HOAc. The reaction mixture was stirred at ambient temperature for 2 hours and placed in the refrigerator overnight. The reaction mixture was allowed to warm to ambient temperature, diluted with toluene and concentrated in vacuo.

The residue obtained was used without further purification.

Example Compound of Formula X is R is -CH?-C=CH The compound resulting from Example 10B (8.16 g) in 1:1 EtOH-H20 (140 ml) was treated with 4 equivalents of NaHSO3 and formic acid (960 pL, 2.4 equivalents) and warmed to -82 After approximately 2.5 hours, the reaction mixture was allowed to cool to ambient temperature, basified to pH 10 with 1 N NaOH solution and extracted with EtOAc. The combined organic extracts were washed, dried and concentrated in vacuo. The crude product obtained was chromatographed on silica gel eluting with 1% MeOH in dichloromethane containing 1% ammonium hydroxide to afford 2.9 g of the title compound which was recrystallized from acetonitrile. 13 C NMR (CDC13) 8 219.7 175.2 102.6 96.2 80.7 80.3 78.8 77.9 76.6, 74.5, 73.9 72.7, 71.0 68.7 65.8, 65.6, 51.8 49.4 OMe), 45.2 44.8 40.2 (NMe2), 38.6 38.5 37.5 35.0 28.6 21.5 Me, 6' Me), 21.2 21.0 (C-6 Me), (18.7, 18.4 (C-2 Me, 6 16.1, 16.0, 12.3 (C-10 Me), 10.6 9.2 (C-4 Me). MS (FAB) m/e 772 (M+H) 810 (M+K) Example 11 Compound of Formula X is R is -CH2-CHOH-CH 2 -N3 To an ambient temperature solution of the compound resulting from Example 4 (100 mg) in 0.75 mL of DMF was added 12 mg of NaN3. The reaction mixture was stirred at ambient temperature approximately 5.5 hours and then an additional 8 mg of NaN3 was added. The reaction mixture was stirred at ambient temperature overnight, heated at 70 oC- °C for 3 hours and then treated with an additional 14 mg of NaN3. The reaction mixture was heated at 60 °C overnight. Four drops of water were added, and the reaction mixture was heated at 80 °C for 4 hours. One equivalent of ammonium chloride was added and heating was continued at 80 oC for 2 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with ethyl acetate and washed with 0.5 N NaOH solution and brine, dried and concentrated in vacuo. The residue obtained was filtered through a silica -97- WO 97/42206 PCTIUS97/07702 S gel plug eluting with 4% MeOH in dichloromethane containing 1% ammonium hydroxide to give 47 mg of the title compound containing trace amounts of DMF. The DMF was removed by dissolving the compound in 1:1 EtOAc-Et20, washing with water followed by brine, drying over magnesium sulfate and concentrating in vacuo to give 45 mg of title compound which was further purified by filtering through silica gel eluting with 4% MeOH in dichloromethane containing 1% ammonium hydroxide to give the title compound. 13

C

NMR (CDC13) mixture of epimers 8 222.8, 221.2 176.6, 175.8 (102.2, 102.1 (96.4, 96.3 80.2, 80.1, 79.4, 78.9, 78.7, 77.6, 77.5, 77.4, 77.0, 76.6, 74.8, 74.7, 72.8, 71.0 70.0, 68.9, 68.6, 67.3, 66.8, 66.2, 65.6, 53.8, 53.2 49.3 OMe), 45.6 45.4, 44.7 40.2 (-NMe 2 38.4, 38.2, 37.9, 37.6, (35.1, 35.0 28.5 21.8, 21.5, 21.2, (21.1, 21.0 20.9, 18.8, 18.2, 16.1, 12.0 (C-10 Me), 12.0, 10.4 9.3, 9.3 (C-4 Me). MS (FAB) m/e 833 (M+H) 871 (M+K) High Resolution Mass Spec m/z Calcd for 7 3

N

4 0 14 833.5123. Found: 833.5137.

Example 12 Compound of Formula X is R is -CH2-CH=N-OH To a solution of the compound resulting from Example 8 (600 mg) in 5 mL of MeOH was added a solution of 80 mg of hydroxylamine hydrochloride and 255 gtL of Nmethylmorpholine in 2 mL of MeOH. The reaction mixture was stirred at ambient temperature for 5 hours and then concentrated in vacuo. The residue obtained was purified by eluting from silica gel using 4% MeOH in dichloromethane containing 1% ammonium hydroxide to give the title compound as a 1:1 mixture of oxime isomers. 13 C NMR (CDC1 3 8 220.8, 219.9 175.4, 175.3 151.7 149.2 (CH=N), 102.4. 102.3 96.3 80.0, 80.0, 79.9, 79.8, 78.8, 78.8, 77.7, 77.3, 77.0, 76.7, 76.5, 76.4, 74.5, 74.4 72.7 72.7, 71.1, 68.8, 68.7, 68.5, 68.5, 66.0, 65.9, 65.4, 61.4, 58.6, 49.4, 49.3 -OCH 3 45.2, 45.2, 44.6, 40.2 (-NMe 2 (38.4, 38.3 38.2 37.4, 37.2 35.0 28.6 21.4, 21.4, 21.2, 21.1, 21.0, 20.9, 20.5, 18.7, 18.6, (18.4, 18.4 (C-8 Me, 6" 16.1, 16.0, 16.0 (C-2 Me), 15.9, 12.2 (C-10 Me), 10.4 9.2 (C-4 Me). MS m/z 791 Example 13 Compound of Formula X is R is -CH-CH 2

OH

To a -78 °C solution of the compound resulting from Example 8 (75 mg) in 1 mL of anhydrous THF was added 1.1 equivalents of L-Selectride dropwise over 2 minutes. The reaction mixture was stirred at -78 °C for approximately one hour and then quenched at -78 °C with an aqueous solution of tris-hydroxymethylaminomethane followed by EtOAc.

98 WO 97/42206 PCT/US97/07702 The organic phase was washed twice with brine, dried over magnesium sulfate and concentrated in vacuo. The crude material (76 mg) was chromatographed on silica gel eluting with 3% MeOH in dichloromethane containing 1% ammonium hydroxide to afford mg of the desired title compound. 13 C NMR (CDC13) 8 222.1 175.9 102.1, 96.3, 83.8, 80.2, 79.6, 78.8, 77.7, 77.0, 74.8, 72.8, 71.1, 68.8, 68.5, 66.1, 66.0, 65.6, 62.0, 49.4, 45.6, 44.7, 40.2 (NMe2), 38.6, 38.1, 37.8, 35.1 28.5 (C- 21.6, 21.5, 21.4, 21.0, 18.7, 18.6, 16.2, 12.1, 10.5, 9.4. MS m/e 778 (M+H) Example 14 Compound of Formula X is R is -CH2-CHNH 2 The compound resulting from Example 12 (160 mg) was subjected to catalytic hydrogenation using a Raney nickel catalyst under 4 atmospheres of hydrogen over hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to afford 159 mg of crude title compound. Purification by column chromatography on silica gel eluting with 7% MeOH in dichloromethane containing 1% ammonium hydroxide afforded 87 mg of the title compound. 13C NMR (CDC13) 8 219.9 175.5 101.6 96.1 79.3 78.9 78.4 77.3 76.3 74.8 72.5 71.1 (68.0, 67.7, 65.6, 64.4, 64.2 48.8 OMe), 45.0 44.4, 40.6, 39.6 (NMe2), (37.9, 37.8 37.5 34.8 29.0 21.0, 20.9, 20.8 20.7, (18.4, 18.1 (C-8 Me, 6" Me), (15.9, 15.4 (C-2 Me, 6 Me), 11.4 (C-10 Me), 10.0 (C-4 Me). MS m/z 777 Example Compound of Formula X is R is -CH2-CN To a solution of the compound resulting from Example 12 (165 mg) in 5 mL of freshly distilled THF was added 2 equivalents of diisopropylcarbodiimide (65 gL) followed by a catalytic amount of CuCl. After stirring approximately 2 hours at ambient temperature, two additional aliquots of diisopropylcarbodiimide (65 gL) were added plus additional CuC1. After 3 more hours, the reaction was complete and the solvent was removed in vacuo to afford the title compound. Mass Spec m/z 773 (M+H) -99- WO 97/42206 PCT/US97/07702 Example 16 Compound of Formula (X X is R is -CH2-Phenyl Example 16A Compound of Formula (XIl: X is =N-O-(1-isopropoxcyclohexy1. R is -CH 2 -Phenyl.

RB is Trimethylsilvl To a 0 oC solution of 30 mL of a 1:1 solution of THF and DMSO containing 5 g of the compound of Formula wherein X is =N-O-(l-isopropoxycyclohexyl) and R is hydrogen was added 1.2 mL of benzyl bromide. A second solution of 30 mL of 1:1 DMSO and THF containing 560 mg of powdered KOH was added in portions over 45 minutes at 0 OC with good stirring. Upon completion of the addition, stir at 0 °C under nitrogen for 1 hour and then allylamine (700 aL) and ethyl acetate were added. The solution was washed wtih water and brine dried over magnesium sulfate, filtered and concentrated in vacuo to afford 6 g of the title compound.

Example 16B Compound of Formula (XII): X is =N-O-(l-isopropoxvcyclohexyl). R is -CH2-Phenyl.

RPis H To a room temperature solution of 6 g of the compound resulting from Example 16A in 65 mL of anhydrous THF was added 14.5 mL of 1 M tetrabutylammonium fluoride.

After several hours, the solvent was removed under reduced pressure and the residue was dried to constant weight. Purification by column chromatography eluting with 4% methanol in dichloromethane containing 1% ammonium hydroxide afforded 2.8 g of the title compound.

Example 16C Compound of Formula (XII): X is =N-OH, R is -CH y-Phenyl. RP.isH To the compound resulting from Example 16B (2.8 g) in 26 mL of acetonitrile was added 14 mL of water followed by 14 mL of acetic acid. The reaction mixture was stirred for -4 hours at ambient temperature and then placed in the freezer overnight. The volatiles were removed in vacuo, and the residue was chased twice with toluene and dried to constant weight to afford 2.73 g of the title compound.

Example 16D Compoundof Formula X is R is -CH2-Phenvl To the compound resulting from Example 16C (2.7 g) in 23 mL of EtOH and water (23 mL) was added 1.4 g of NaHS03. This was followed by 292 tL of formic acid, and -100- WO 97/42206 PCT/US97/07702 the reaction mixture was warmed to 80 OC. After approximately 90 minutes, the reaction mixture was allowed to cool to ambient temperature, basified to pH -10-11 with 2 N NaOH solution and extracted with ethyl acetate. The combined organic extracts were washed with water followed by brine, dried over magnesium sulfate, filtered and concentrated in vacuo.

The crude material (1.95 g) was chromatographed on silica gel eluting with 1% methanol in dichloromethane containing 1% ammonium hydroxide followed by 2% methanol in dichloromethane containing 1% ammonium hydroxide to afford 715 mg of the title compound. Further purification was effected by chromatography on silica gel eluting with 2% ammonium hydroxide in dichloromethane followed by 2% methanol in dichloromethane containing 1% ammonium hydroxide to afford 435 mg of the title compound. 13 C NMR (CDC13) 8 219.28, 174.69, 139.20, 128.51, 127.95, 127.12, 102.20, 96.42, 80.14, 79.80, 78.96, 77.79, 77.42, 77.00, 76.56, 74.77, 72.84, 71.11, 68.75, 68.56, 66.39, 66.21, 65.61, 49.41, 45.15, 44.62, 40.27, 38.02, 37.91, 35.19, 28.54, 21.95, 21.56, 21.53, 21.28, 19.2, 18.82, 16.25, 16.09, 12.24, 10.61, 9.56. MS (FAB) m/e 824

(M+H)

Example 17 Compound of Formula X is R is -CH-CH=CH-Phenyl- The title compound was prepared by the procedures described in Example 16 substituting 3-phenyl allyl bromide for benzyl bromide. For conversion of the oxime to the ketone, the reaction mixture was heated about 3 hours and then placed in the freezer overnight. Chromatography on silica gel eluting with 1% methanol in dichloromethane containing 1% ammonium hydroxide afforded -700 mg (17% yield for three steps) of the title compound. H. Res. MS: 850.5338.

Example 18 Compound of Formula X is R is -CH-CH=N-O-CH3 To a room temperature solution of 150 mg of the compound resulting from Example 8 in 1 mL of methanol was added a solution of 14 mg of methoxylamine hydrochloride in 0.5 mL methanol containing 64 jiL of N-methyl morpholine in one portion. The reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for about 6 hours and then treated with 0.75 equivalents (12 mg) of methoxylamine hydrochloride. The reaction mixture was stirred at ambient temperature for 1 hour and then placed in the refrigerator overnight. The volatiles were removed under reduced pressure to afford 215 mg of crude title compound. Purification by column chromatography on silica gel eluting with 1% methanol in dichloromethane containing 1% ammonium hydroxide afforded 120 mg of the title compound as a 1:1 syn:anti mixture. 13 C NMR (CDC13) 8 219.3, -101- WO 97/42206 PCT/US97/07702 218.4, 173.8, 173.7, 157.9, 149.5, 146.8, 100.8, 100.7, 94.7, 94.5, 93.0, 78.4, 78.2, 77.3, 77.1, 76.2, 75.9, 75.4, 75.0, 74.9, 74.8, 72.9, 72.7, 71.2, 71.1, 69.4, 67.2, 67.1, 67.0, 65.3, 64.5, 64.4, 64.0, 59.9, 57.3, 47.8, 47.8, 44.8, 43.7, 43.6, 43.0, 38.6, 36.8, 36.7, 36.7, 35.7, 33.4, 26.9, 19.9, 19.8, 19.4, 18.9, 17.1, 16.9, 16.8, 14.4, 14.4, 10.6, 8.9, 8.8, 7.6, 7.5. MS (FAB) m/e 805 (M+H) Example 19 Compound of Formula X is R is -CH-CH=N-O-CH 2 -Phenvl The title compound was prepared as a 1:1 syn:anti mixture by the procedures described in Example 18 substituting O-benzyl hydroxylamine hydrochloride for methoxylamine hydrochloride to afford 118 mg 13 C NMR (CDC13) 8 219.3, 218.5, 173.8, 173.7, 149.8, 147.6, 136.6, 126.5, 126.5, 126.2, 125.8, 125.8, 100.8, 100.8, 94.7, 94.5, 93.0, 78.5, 78.4, 78.2, 77.2, 76.2, 76.2, 75.8, 75.4, 75.0, 74.9, 74.2, 74.0, 72.8, 72.7, 71.2, 71.1, 69.4, 67.2, 67.1, 67.0, 65.3, 64.4, 64.4, 60.1, 57.5, 53.8, 47.8, 47.8, 44.8, 43.6, 43.0, 38.6, 36.8, 36.8, 36.7, 36.7, 35.6, 33.4, 33.4, 26.9, 19.9, 19.8, 19.8, 19.5, 19.4, 19.0, 17.1, 17.0, 16.8, 16.8, 14.4, 14.4, 10.6, 10.6, 8.9, 7.6. MS (FAB) m/e 881 (M+H) Example Compound of Formula X is R is -CH-CH=N-N(CH3)2 The title compound was prepared by the procedures described in Example 18 substituting N,N-dimethyl hydrazine for methoxylamine hydrochloride. Purification by column chromatography eluting with 2% methanol in dichloromethane containing 1% ammonium hydroxide afforded 115 mg of the title compound as a single (syn or anti) isomer. 13 C NMR (CDCl3) 8 217.8, 173.5, 132.4, 100.5, 94.5, 92.7, 78.1, 77.4, 76.0, 75.6, 75.2, 74.7, 74.6, 72.6, 70.9, 69.2, 66.7, 64.1, 63.7, 63.0, 47.5, 43.4, 42.7, 41.0, 38.4, 36.6, 36.5, 35.4, 33.1, 26.7, 19.6, 19.6, 19.4, 19.2, 16.8, 16.6, 14.3, 14.0, 10.4, 8.8, 7.4. MS (FAB) mle 818 (M+H) Example 21 Compound of Formula X is R is -CH2-CH=N-NH(CH31 The title compound was prepared by the procedures described in Example 18 substituting N-methyl hydrazine for methoxylamine hydrochloride. Purification by column chromatography eluting with 2% methanol in dichloromethane containing 1% ammonium hydroxide afforded 89 mg of the title compound as a single pure isomer of unknown stereochemistry. 13 C NMR (CDCl3) 5 219.7, 175.5, 136.2, 102.5, 96.5, 80.1, 79.4, 79.1, 77.9, 77.2, 77.0, 76.7, 76.5, 74.5, 72.8, 71.1, 68.7, 66.1, 65.7, 64.4, 49.4, 45.3, -102- WO 97/42206 PCT/US97/07702 44.6, 40.3, 38.6, 38.5, 37.4, 35.1, 34.8, 28.6, 21.5, 21.5, 21.3, 21.0, 18.8, 18.5, 16.2, 15.9, 12.3, 10.7, 9.2. MS (FAB) m/e 804 (M+H) Example 22 Compound of Formula X is R is -CH2-CH=N-(4-MorpholinYD The title compound was prepared by the procedures described in Example 18 substituting N-amino morpholine for methoxylamine hydrochloride. Purification by column chromatography eluting with 5% methanol in dichloromethane containing 1% ammonium hydroxide followed by re-chromatography eluting with 2% methanol in dichloromethane containing 1% ammonium hydroxide afforded 125 mg of the title compound as a single pure isomer of unknown stereochemistry. Diagnostic peaks 1H NMR (CDC13, 500 MHz) 5 0.84 3H), 2.29 6H), 3.12 4H), 3.34 3H), 3.85 4H), 4.50 (d, 1H), 4.92 1H), 5.06 (d of d, 1H). MS (FAB) m/e 860 (M+H) Example 23 Compound of Formula X is R is -CH2-CH=N-NH(Phenyl) The title compound was prepared by the procedures described in Example 18 substituting N-phenyl hydrazine for methoxylamine hydrochloride. Purification by column chromatography eluting with 1% methanol in dichloromethane containing 1% ammonium hydroxide afforded 50 mg of the title compound as a single pure isomer of unknown stereochemistry. IMS (FAB) m/e 866 (M+H) Example 24 Compound of Formula X is R is -CH2-CH=N-N(Phenvl)2 The title compound was prepared by the procedures described in Example 18 substituting N,N-diphenyl hydrazine for methoxylamine hydrochloride. Purification by column chromatography eluting with 2% methanol in dichloromethane containing 1% ammonium hydroxide afforded 156 mg of the title compound as a single pure isomer of unknown stereochemistry. Diagnostic peaks 1 H NMR (CDCl3, 300 MHz) 8 7.07-7.39 (m, 10H), 6.46 1H). MS (FAB) m/e 942 (M+H) Examples 26-105 Compounds having Formula wherein X is 0. R is CH2-CH(OH)-CH-R a d RY is as shown In accordance with the procedures of Examples 5, 6, 7 or 210, except replacing the reagent amines from those examples with the appropriate amine, the compounds of Examples 26-105, which are compounds having Formula wherein -103- WO 97142206 PCT1US97107702 X is 0, R is CH 2 -CH(OH)-CH2-RV, and RV is as shown in Table 1 below, were prepared.

RV

00 I HI Table 1 Examples 26-105 Compounds having Formula wherein X is R is CW-CH(OH-CH9-RV and is as shown MS analysis Exam. RV No.

26 molecular formula Calcd.

exact mass MS analysis .1 I 1 27 rl-NJO

C

49

H

82 N2014

C

5 0

H

85 N3014 922.6 I i 922.1i, 461.4 951.6 952.0). 4765.2 1 .4 I 28 1Y

C

5

OH

86 N2014 938.6 937.h. 470.2 t 1~ 98. 98.. 9.

29 31 3 2

OH

C

54

H

86

N

2 014 986.6 985.h. 493-h

_I

911.1, 456.3

C

48

H

82 N2014 910.6 911.1, 456.3 I

C

4 9 Hg4N2015 940.6 939.8, 470.9 i

C

45

H

8 3N3014 889.6 889.0, 445.3 t 33 1 hj

C

45

H

8 4N2014 876.6 877.0, 439.4 34

S&;

C

48

H

9 ON2014 918.6 918.5, 459.9 I I

J

-104- SUBSTITUTE SHEET (RULE 26) PCT/11S97/07702 WO 97/42206 0 I I F x0 C44H 8 N2014S 892.5 891.8, 447.0 I I i 36 37 38 39 41 42 43 44 46 47 48 49 51

N.

ro1

C

46

H

8 2 N2014 886.6 886.1, 444.2 46H86N2014 890.6 889.9, 446.2

C

4 7 H84N2016 932.6 931.8, 467.3

I

C

4 6 H84N2O14 888.6 887.6, 445.0 4. I C44H 79 N3014 873.6 872.8, 437.3

S

C

4 7

H

8 6N2014

C

4 7

H

8 6N2014 902.6 901.9, 451.7

I

902.6 901.9, 451.7 t

C

49 H88N2014

C

50

H

8 4FN3014 928.6 928.0, 465.0 .1 .1 969.6 970.2, 485.2 L 4. 4.

C

5 1 H88N2O14 952.6 952.4, 476.8 I. i

C

5 1 H8 7 N3014 965.6 964.8, 483.4 J, .I OMe 4 OMe 50e

ONO

C

51

H

88 N2016 984.6 985.1, 492.8

C

46

H

8 5 N3014 903.6 904.2, 452.0 C50H91N3014 957.7 957.4, 479.1

C

48 H88N2014 916.6 915.9, 458.6 I I

C

46

H

8 6N2014 890.6 889.9, 446.0 -105- SUBSTITUTE SHEET (RULE 26) PCTIUS97/07702 WO 97/42206 0 52 53 54 56 57 58 59 61 62 63 64

CF

3 0.

OH

r c I; .0-OH

OH

OMe ome

(>C

~N02 rK m

C

5 1

H

8 4F3N3014

C

46 H4N2O14

C

47

H

8 6N2014 902.6 902.1, 452.0

C

52

H

8 7 N3O16 1009.6 1010.0, 505.7

C

5 1

H

8 5 C1N2015 1000.6 1000.9, 501.4 C44H8ON2O15 876.6 877.1, 439.1

C

5 1 H86N2015 966.6 965.6, 483.8

C

48 H86N2014 914.6 915.0, 457.8

C

45

H

8 2N2016 906.6 907.3, 453.9

C

46 H85N3015 919.6 920.2, 460.6

C

46 H86N2016 922.6 923.3, 461.8 C44H 8 2N2O14 862.6 863.2, 431.9

C

4 9 H84N4014 952.6 952.0, 476.9

C

5 oH&iN4O16 996.6 996.9, 499.2

C

52

H

89 N3014 979.6 980.2, 490.4

C

5 lH 86 C1N3O14 999.6 999.1, 500.9 1019.6 1020.1, 510.0 888.6 889.4, 444.8 66 67 68 <O C 52 H89N3014 979.6 980.0, 490.2 -106- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT1US97/07702 69 I C 52

H

89 N3014 979.6 978.8, 490.3 71 72 73 74 76 77 78 79 81 82

CN.

OMe <,rrliJ OMe .~)OMe r~QOMe ~NOMe

CI

wfN LCI NrQ

O

ome clc u~cl ull~

SOH

1

C

5 iHg4N4014 976.6 977.2, 488.8

C

52 H89N3016 1011.6 1010.7, 506.2 C5 1 H87N3015 981.6 982.1, 491.1

C

52 H89N3016 1011.6 1012.2, 506.3

C

52

H

8 9N3014 979.6 978.8, 490.4

C

50

H

83 C12N3014 1019.5 1019.8, 510.8

C

50

H

83 C12N3014 1019.5 1019.9, 510.6

C

5

H

8 4FN3014 969.6 970.2, 485.2

C

46 H8 5 N3014 903.6 902.9, 452.3 C50H8 4 C1N3014 985.6 984.8, 493.7

C

5 oHg4N4O16 996.6 997.0, 498.9

C

4 8

H

87

N

3 016 961.6 960.6, 481.2 ~1

C

4 9

H

8 3N3016 C44H 82 N2015 969.6 968.7, 485.7

I

1878.6 1 878.5, 440.0 I I

I

-107- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 84 86 87 88 89 Nr9"

'K

OH

nOMe r~cl NclNbo NcrQ 4 .f

C

5 0 H94N4014 974.7 1973.8, 487.6 4

C

52 Hg9N3014

C

52 H89N3014 979.6 979.4, 490.3 979.6 1 978.8, 490.4 I

C

4 9 H4N2015 940.6 941.2, 470.6 I. I

C

5 1

H

8 7

N

3 014 965.6 965.9, 483.8 I 4 9

C

52 H89N3014 979.6 978.8, 490.6 91 92 93 94 96

C

52 H89N3014 979.6 980.1, 490.3

C

52

H

89 N3015 995.6 994.9, 498.5

C

52

H

9 4N4014 998.7 999.2, 499.7

C

52

H

89 N3014 979.6 978.8, 490.6

C

43 H8oN2014

C

55 H95N3014 848.6 11021.7 848.0, 425.1 1020.8, 511.2

C

5 oH 8 4C1N3014 1985.6 986.1, 493.9 I r N4o" 975.6 1 974.8, 488.5

C

4 9 H89N3016 I 4 98 99 rl-W

C

5 1 H 86 CN3014 999.6 999.89, 500.8 I

C

57 H91N3014 1041.7 1041.2, 521.8 -108- SUBSTITUTE SHEET (RULE 261 PCTIUS97/07702 WO 97/42206 0 100 102 103 104 105

~N

OMe

F

F

C

5 ocj9N3O14 1 957.6 957.0, 479.7 L I r 952.7, 477.2

C

4 8

H

8 3N5014 953.6 952.7, 477.2 C47H7N3 1 933.6 1934.2, 467.11 C57H8F2N3 1T1077.6 1076.5, 539.4

I

C

47 H85N3016 946.8, 474.5 Exampies 16-153 Compounds having Formula wherein X is 0: R is CH2-CH2-Ryk and R M is as shown Treating the compound of Example 8 with an appropriate reagent amidne in the presence of sodium cyanoborohydride in methanol and acetic acid, the compounds of Examples 106-153, which are compounds having Formula wherein X is 0, R is

CH

2

-CH

2 -RW; and RW is as shown in Table 2 below, were prepared.

-109- SUBSTITUTE SHEET (RULE 26) PCT/US97/07702 WO 97/42206 Table 2 Examples 106-153 nmnnnnds havin Formula wherein X is 0: R CH2-CH2-RWi and R

W

is as shown Exam. RW molecular formula Calcd. MS analysis No. exact mass 106

C

47

H

80 N2013 880.6 881.4, 880.2, 440.9 107

C

4 8 H80N2013 892.6 893.5, 892.1, 447.2 108 )Qj C 50

H

85 N3014 951.6 953.2, 951.1, N OMe. 477.1, 476.3 109

C

51

H

85 N3015 979.6 980.1, 979.1, o 0 490.6 110

C

48

H

82 N2013 894.6 895.4, 894.1, 448.1 111

C

47

H

7 8N2013 878.6 879.2, 878.1, 439.9 112 N, C 48

H

8 2N4013 922.6 923.5, 922.1, N 462.0 113 3 C 50

H

82

F

3 N3013 989.6 990.3, 989.0, N) 3 495.8 114

C

49

H

83 N3013 921.6 922.4, 921.3, 461.6 115

C

49

H

82 FN3013 939.6 940.7, 939.1, 470.5 116

C

51

H

82 N2013 930.6 931.3, 930.1, 777.1, 778.4, 466.6, 465.6 117

C

48

H

8 0N2013 892.6 892.1, 446.8 -110- SUBSTITUTE SHEET (RULE 26) PCT/US97/07702 WO 97/42206 118 F

C

4 9

H

81 FN2013 924.6 925.4, 924.3, S923.4, 462.8 119 ci C 4 9

H

8 2CIN3013 955.6 958.4, 957.3, r 956.2, 955.0, 479.1 120 1 C 51

H

87 N3013 949.6 950.6, 949.3, 475.4 121 OMe C 5 1

H

8 7N3015 981.6 982.5, 981.1, r- OMe 491.7 OMe 122

C

50

H

82 N4013 946.6 947.4, 946.1, ,Kr) CN 474.3 123 c C 4 9

H

81 C2N3013 989.5 992.3, 991.2, r"NP cl 990.1, 496.8, ,NNJ _495.4 124 <C.NJ"

C

5 1 H87N3013 949.6 950.4, 949.1, .475.5 125 1 cF3 C 50

H

82

F

3 N3013 989.6 990.0, 989.0, 495.7 126

C

5 1

H

8 7N3013 949.6 949.9, 949.0, 475.4 127 O.OMe C 5 1

H

8 7N3014 965.6 966.5, 965.1, 483.5 128

C

5 1

H

87 N3013 949.6 950.2, 949.4, 475.7 129

C

51 H87N3013 949.6 950.5, 949.1, 476.2, 475.3 130 No 2

C

4 9

H

82

N

4 015 966.6 967.4, 966.1, _484.2 111- SUBSTITUTE SHEET (RULE 26) PCT[US97/07702 WO 97/42206 0 r1 131 132 133 134 135 cl

'NN)

I CS 1

H

8 7N3O14 1965.6 966.3, 964.9, 483.6 I

C

5 oH81CIF3N301 1023.5 1026.3, 1025.3, 1024.0, 11022.9, 512.9 C5oH 8 5N 3 013S 967.6 968.4, 967.2, N) SMe j 484.4 1 1 r c RAO 2

C

49

H

8 2N4015 966.6 967.3, 966.2, 484.0 1 I 136 137 138 139 140 141 142 K cl OMe OMe

F.

F

C

5

H

87

N

3 013 949.6 4 I 950.5, 949.3, 475.3

C

5 0

H

84 C1N3013 969.6 972.4, 971.5, 970.2, 969.1, 486.1 4. I

C

5

H

87 N3015 981.6 982.4, 981.1, 492.1, 491.3

C

49 Hg 1 F2N3013 957.6 958.3, 957.0, 479.7

C

4 9

H

8 2 FN3013 939.6 940.4. 939.1, 470.4

C

5

H

8 5N3013 935.6 936.4, 935.1, 468.6 I I T <NrQ

C

5 1

H

8 7 N3014 965.6 966.1, 965.1, 483.4 '4~:N3 -4 t

C

47

H

81 N5013 923.6 I 1 143

CI.

C

49

H

82 C1N3013 955.6 924.4, 923.1, 463.1, 462.2 958.4, 957.3, 956.2, 955.0, 478.6 .11_ -112- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 0 144

C

49

H

82 CIN3013 955.6 958.4, 957.3, c 956.4, 955.3, 479.1 145 ifY c C50H81CIN2013 952.5 955.3, 954.3, 953.2, 952.0, 477.1 146 OMe C5 1

H

87 N3015 981.6 982.4, 981.0, OM e 491.4 147 o C50H 83 N3015 965.6 966.3, 964.9, 0 483.8 148

C

56 H89N3014 1027.6 1028.3, 0 1027.0, 514.3 149 c1 C 50

H

83 C1 2 N3014 1019.5 1022.3, rKN cl 1021.2, S 1019.9, 1018.7, 510.8 150 0 C 5 2

H

8 9N3014 979.6 979.0, 490.4 151

C

5 0H 85 N3013 935.6 936.4, 468.7 152 PJOMe C 52

H

89

N

3 016 1011.6 1012.1, 1..OMe 1011.1, 507.0, 506.1 153

C

5 1

H

87 N3013 949.6 950.4, 949.2, 475.8 Examples 154-164 Compounds having Formula wherein X is 0, R is CH2-CH=N-RXand RX is as shown Treating the compound of Example 8 according to the procedures of Example 12, except substituting the appropriate substituted hydroxyl amine reagent for the unsubstituted hydroxylamine reagent of Example 12, the compounds of Examples 154-164, which are 113- SUBSTITUTE SHEET (RULE 26) WO 97/42206 WO 9742206PCT/US97/07702 compounds having Formula wherein X is 0, R is CH2-CH=N-RX and RX is as shown in Table 3 below were prepared.

Table 3 Examples 154-164 Compounds having Formula MX wherein X is 0. R is CH2-CH=N-RX and RX is as shown Exam. RX molecular formnula Calcd. MS analysis No. exact mass 154 C41H 75

N

3 0 13 817.5 818.4, 817.3, 409.6 155 C4 1

H

7 1

N

5 0 13 841.5 841.6, 421.6 156

C

4 5

H

8 1

N

3 0 13 871.6 871.9, 436.5 157

H

157-C C42H 74

N

4 0 13 842.5 842.7 158 C44H 79

N

3 0 13 857.6 857.5, 429.4 159

C

46

H

77

N

3 0 13 879.5 880.3, 879.1 160 C43H 7 7

N

3 0 13 835 844.3, 843.4 161 r~JC 48

H

79

N

3 0 13 905.6 906.3, 904.9, 454.1, 453.2 162 H

C

4 5

H

73

N

5 0 17 955.5 956.4, 955.1 02__ N0 2 163

C

47

H

77

N

3 0 14 907.5 908.3, 907.2 -114- SUBSTITUTE SHEET (RULE 26) PCTIUS97/07702 WO 97/42206 *h w 164 N.HJ C44H73N3015 883.5 884.3, 883.2

O

Example 165 Compound of Formula Rb isHR is H Rd is phenylmethyloxycarbonyl; RP is methoxv: R f is H; R is -CH2-CH=CH9 Step 165a. 2'-acetvl-6-O-allvl erythromvcin A A solution of 6-0-allyl erythromycin A (10 g, the compound of Formula (X) wherein X is =0 and R is -CH 2 -C=CH2, from Example 10 step c above) and triethylamine (2.25 mL) in dichloromethane (50 mL) was cooled to 0 OC and flushed with nitrogen.

Acetic anhydride (2.4 mL) was added, the solution was stirred at 0 OC for 5 minutes, then the ice bath was removed and the mixture was stirred for 5 hours at ambient temperature.

The mixture was quenched by addition of 1.5 M aqueous KH2PO4 (50 mL), then extracted with ethyl acetate. The organic phase was washed with water and brine, then dried over MgSO4. The solvent was removed under vacuum, and the residue was dried. The residue was crystallized from acetonitrile to give the title compound (5.66 g).

Step 165b. 2'-acetvl-4'-(phenylmethyloxvcarbonvl)6--allyl erythromycin A To a solution of 2'-acetyl-6-O-aUyl erythromycin A (5 g, from step 165a) in dry dichloromethane (50 mL) was added DMAP (3 and the solution was cooled to -40 OC.

The solution was flushed with nitrogen, and benzyl chloroformate (3 mL) waa added over 45 minutes. Then additional DMAP (585 mg) and benzyl chloroformate (0.585 mL over minutes) was added. The mixture was stirred under nitrogen for 0.5 hours at -40 OC and at °C for 40 hours, then diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The organic phase was separated, washed with water and brine, then dried over MgSO4. The solvent was removed, the residue (6.5 g) was triturated with ethyl acetate, and the solvent was washed, dried and removed under vacuum. The residue was crystallized from acetonitrile, then purified by chromatography on mixed alumina and silica gel to give the title compound (4.6 g).

Step 165c. Compound of Formula R is H; R i R is phenylmethyloxycarbonyl;

R

e is methoxv: Rf is acetvl: R is -CH2-CH=CH9 To a solution of 2'-acetyl-4'-(phenylmethyloxycarbonyl)-6-O-alyl erythromycin

A

g, from step 165b) in THF (90 mL) at -40 OC was added 1 M sodium bis(trimethylsilyl)amine (5.25 mL), and the mixture was stirred for 10 minutes. To this was added carbonyldimidazole (2.7g) in THF over 45 minutes, then the ice bath was removed 115- SSUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 and the mixture was stirred at ambient temperature for 40 minutes. The mixture was cooled to 0 OC, quenched with 1 M aqueous KH 2

PO

4 then extracted with ethyl acetate. The organic phase was washed with water and brine, then dried over MgSO4. The solvent was removed under vacuum, and the residue was dried. The residue was crystallized from acetonitrile, then purified by chromatography on silica gel, eluting with 25-50% acetone/hexane to give the title compound (2.65 g).

Step 165d. Compound of Formula Rh is HRsH: Rd is phenvlmethyloxycarbonyl; R is methoxv: Rf is H: R is -CH?-CH=CH, A solution of the compound from step 165c (400 mg) in methanol (30 mL) was stirred at room temperature for 20 hours and at 50 °C for 6 hours. The solvent was removed to give the title compound. H. Res. MS 934.5176 Example 166 Compound of Formula Rb is H; R is H Rd is hydroxy; Re is methoxy; Rf is H R is -CH2-CH=CH? To a sample of the compound from Example 165 in methanol was added 10% Pd/C (450 mg), and the mixture was shaken under 1 atm of hydrogen for 2.5 hours. The mixture was filtered, and the solvent was removed. The residue was purified by chromatography on silica gel, eluting with 25-50% acetone/hexane to give the title compound. H. Res. MS 802.4941 Example 167 Compound of Formula Rhj i s HL RR is phenylmethvloxycarbonl;

R

e is methoxv: Rf is acetvl: R is -CH?-CH=CH? A solution of the compound of Example 165 step c (3.6 g) and DBU (4.4 mL) in benzene (136 mL) was heated at reflux for 8 hours. The solvent was removed under vacuum, and the residue was dissolved in ethyl acetate. This solution was extracted with 1M NaH 2 PO4 and washed with brine, then dried over MgSO4. The solvent was removed, and the residue was purified by chromatography on silica gel, eluting with acetone/hexane to give the title compound (3.3 g).

-116- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 Example 168 Compound of Formula (VII): W is -NH-:Rh is H R is H: Rd is phenylmethvloxycarbonyl; R is methoxv: RI is H: Rg is H: R is propvl Step 168a. Compound (28) of Scheme V: 2'-RP is acetvl; 4"-RP is phenvlmethvloxycarbonvl; R is -CH-CH=CH2 To a -10 OC solution of the compound of Example 167 (3.3 g) in THF (60 mL) flushed with nitrogen was added 60% NaH (284 mg), and the mixture was stirred at -10 °C for 15 minutes. The mixture was warmed to 0 OC, and a solution of CDI (1.7 g) in THF (30 mL) was added over 15 minutes. The mixture was then stirred at room temperature under nitrogen for 2.5 hours. The mixture was cooled to 0 quenched with ethyl acetate, and saturated aqueous sodium bicarbonate solution was added. The organic phase was separated, washed with brine and dried over MgSO4. The solvent was removed, and the residue was purified by chromatography on silica gel, eluting with 35% acetone/hexane to give the title compound (3.2 g).

Step 168b. Compound of Formula (VII): W is -NH-Rb HRsis H Ris phenvlmethvloxycarbonvl;

R

e is methoxv: R f is H: R is H; R is propyl To a sample of the compound from step 168a (100 mg) in DMF (1 mL) was added hydrazine (0.048 mL), and the mixture was stirred at 60 °C under nitrogen for 43 hours.

The mixture was diluted with ethyl acetate, then washed with aqueous sodium bicarbonate and dried over MgSO4. The solvent was removed, and the treatment with hydrazine was repeated, heating for 24 hours at 60 The mixture was diluted with ethyl acetate, then washed with aqueous sodium bicarbonate and dried over MgS04. The solvent was removed, and the residue was purified by chromatography on silica gel, eluting with 1% methanol/dichloromethane containing 0.5% NH 4 0H to give the title compound (136 mg).

H. Res. MS 950.5594 Example 169 Compound of Formula (VII: W is R is HR is HRdis H R£ is methoxy: Rf is H: R is H: R is propvl To a sample of the compound from Example 168 (73 mg) in methanol (2 mL) was added 10% Pd/C (60 mg), and the mixture was shaken under 1 atm of hydrogen for 2 hours. The mixture was filtered, and the solvent was removed to give the title compound (56 mg). H. Res. MS 816.5198 -117- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 Example 170 Compound of Formula (VII): W is Rh is HL R is H Rd is phenvlmethyloxycarbonyl; R£ is methoxv: Rf is H: Rg is H: R is -CH9-CH=CH2 To a solution of the compound of Example 168 step a (3.3 g) in acetonitrile (26 mL) was added hydrazine (0.206 mL), and the mixture was stirred at room temperature for 22 hours. The mixture was diluted with ethyl acetate, and this solution was washed with water and brine and dried over MgSO4. The solvent was removed, and the residue was dissolved in methanol and stirred under nitrogen at room temperature for 66 hours. The solvent was removed to give the title compound containing a mixture (2.20 g) of the C10 epimers. This material was dissolved in methanol (15 mL) and stirred at ambient temperature in a sealed tube with 2 M NH 3 in methanol (15 mL) for 5 days. The solvent was removed, and the residue (2.18 g) was purified by chromatography on silica gel, eluting with 7% methanol/dichloromethane containing 3% NH 4 0H to give the title compound (1.86 H.

Res. MS 948.5440 Example 171 Compound of Formula (VII): W is absent: Rh is H Rs Rd is phenvlmethvloxvcarbonyl: R£ is methoxv: Rf is acetvl: Rg is 4-phenvlbutvl: R is -CH,-CH=CH, To a solution of the compound of Example 168 step a (2.0 g) in acetonitrile (22 mL) was added 4-phenylbutylamine (2.5 mL), and the mixture was stirred at room temperature for 66 hours. The solvent was removed, and the residue was purified by chromatography on silica gel, eluting with 1% ethyl acetae/hexane containing 1% NH40H to give the title compound (2.14 g).

Example 172 Compound of Formula (VII: W is absent: Rh isH is H R is phenvlmethvloxvcarbonvl: R9 is methoxv: Rf is H Rg is 4-phenylbutvl: R is -CH?-CH=CH, A solution of the compound of Example 171 (400 mg) in methanol (15 mL) was stirred under nitrogen at room temperature for 4 days. The solvent was removed, and the residue (2.18 g) was purified by chromatography on silica gel, eluting with acetone/hexane to give the title compound (355 mg). MS 1065 (M+H) -118- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 Example 173 Compound of Formula (VII): W is absent: Rh is H: R is H-Rd is

H

Re is methoxy: Rf jRg is H Ris 4-henvlbutvl R is propvl To a sample of the compound from Example 172 (220 mg) in methanol (4 mL) was added 10% Pd/C (200 mg), and the mixture was shaken under 1 atm of hydrogen for 3 hours. The mixture was filtered, and the solvent was removed to give a compound which was purified by chromatography on silica gel, eluting with 1% methanol/dichloromethane containing 10% NH 4 0H to give the title compound (148 mg). Anal. Calcd. for

C

51

H

84 N2013: C, 65.63; H, 9.07; N, 3.00; Found: C, 65.25; H, 9.00; N, 2.87. H. Res.

MS 933.6059 (M+H) Example 174 Compound of Formula (VII): W is absent; Rh is H; R jisj1 Rd is phenvlmethloxvcarbonyl: Re is methoxv: Rf is acetyvl R is 4-Dhenvlbutvl: R is -CH2-CH=CH-(3-auinolinvl) To a sample of the compound from Example 171 (500 mg, 0.452 mmol) in acetonitrile (5 mL) were added 3-bromoquinoline (188 mg, 0.904 mmol), palladium acetate (21 mg, 0.094 mmol), tri-(o-tolyl)phosphine (55 mg, 0.181 mmol) and triethylamine (0.126 mL, 0.904 mmol). The mixture was cooled to -78 OC, degassed, sealed in a tube under nitrogen, and heated at 50 OC for 2 hours, and at 80 °C for 14 hours. Additional palladium acetate (20 mg, 0.094 mmol) and tri-(o-tolyl)phosphine (20 mg) were added, and the mixture was heated at 100 °C for 12 hours. Additional 3-bromoquinoline (0.046 mL) and triethylamine (0.065) were added, and the mixture was heated at 100 °C for 24 hours.

The mixture was cooled and diluted with ethyl acetate, then washed with saturated brine, 1M tris(hydroxymethyl)aminomethane, brine and dried over MgSO4. The solvent was removed to give a compound which was purified by chromatography on silica gel, eluting with 25-40% acetone/hexane to give the title compound (444 mg).

Example 175 Compound of Formula (VII): W is absent Rh is H: R is H: Rd is phenvlmethvloxvcarbonyl; Re is methoxv: Rf is H Rg is 4-phenvlbutyl; R is -CH2-CH=CH-(3-ouinolinvl) A solution of the compound of Example 174 (444 mg) in methanol (20 mL) was stirred under nitrogen at 50 °C for 7 hours and at room temperature for 16 hours. The solvent was removed, and the residue (420 mg) was purified by chromatography on silica gel, eluting with 1% methanol/dichloromethane to give the title compound (170 mg).

H. Res. MS 1192.6678 -119- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 Example 176 Compound of Formula (VII): W is absent: Rh is H: RisL H Rd is H; R e is methoxv: Rf R is R -phenvlbutl: R is -CH2-CH2-CH2-(3-quinolil) To a sample of the compound from Example 175 (130 mg) in methanol (6 mL) was added 10% Pd/C (100 mg), and the mixture was shaken under 1 atm of hydrogen for 17 hours. The mixture was filtered, and the solvent was removed to give a compound which was purified by chromatography on silica gel, eluting with 2% methanol/dichloromethane containing 1% NH 4 0H to give the title compound (41 mg). H. Res. MS 1060.6453 Example 177 Compound of Formula RA is hydroxy Rh is H:Ris H; R s Re is methoxv: R f is H: R is -CH2-CH=CH? A mixture of 6-0-allyl erythromycin A (30 g, prepared according to Example step c above), trethylamine (70 mL) and ethylene carbonate (24 g) was heated at 95 OC under nitrogen with stirring for 66 hours. The mixture was cooled and diluted with ethyl acetate and extracted with water. The organic phase was washed with water and brine and dried over MgSO4. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with 2% methanol/dichloromethane containing 1 '7

NH

4 0H to give the title compound (20.9 The compound was crystallized from acetonitrile with a yield of 14.6 g in the first crop. MS 756 (M+H) Example 178 Compound of Formula (VII): W is absent: Rb Ri i H is R is methoxv: Rf i H Rg is H: R is -CH-CH=CH2 Step 178a. Compound of Formula Ra is hvdrox Ris H R is H R is trimethvlsilvl: R is methox Rf is trimethvlsilvl: R is -C-H-CH=CH? To a solution of the compound from Example 177 (12.2 g) in acetonitrile (90 mL), THF (20 mL) and dichloromethane (6 mL) was added hexamethyldisilazane (10.1 mL), and the reaction was stirred at room temperature for 44 hours. The solvents were then removed under vacuum to give the title compound (15.1 g).

120- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 Step 178b. Compound (28) of Scheme V: 2'-RB is trimethylsilyl: 4"-RU is trimethylsilyl:

R

is -CH9-CH=CH To a -10 °C solution of the compound of step 178a (15.1 g) in freshly distilled THF (200 mL) was added 60% NaH (1.3 and the mixture was stirred for 10 minutes then warmed to 0 To this solution was added carbodiimidazole (6.5 g) in THF (100 mL) over 15 minutes, then the mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0 diluted with ethyl acetate and quenched with 5% aqueous sodium bicarbonate solution. This mixture was extracted with ethyl acetate, and the organic phase was washed with water and brine, then dried over MgSO4. The solvent was removed to give the title compound.

Step 178c. Compound of Formula (VII): W is absent: Rb is H: R is R d is trimethylsilyl: RR is methox Ris rim R is -CH-CH=CH A solution of the compound from step 178b (17.5 g) in acetonitrile (250 mL) and liquid ammonia (250 mL) at -78 °C was sealed in a tube and stirred at room temperature for 24 hours. After cooling to -78 OC the seal was broken, and the solution was stirred at room temperature to release the excess ammonia. The solvent was then removed under vacuum to give the title compound.

Step 178d. Compound of Formula (VII): W is absent: Rh is H: R- is H: RdiH Re is methoxy: Rf is H: R R is -CH2-CH=CH9 To a solution of the compound of step 178c (17 g) in acetonitrile (200 mL) at 0 OC was added a solution of HF 2.3 mL) in acetonitrile (10 mL) over one minute. The mixture was stirred at room temperature for 1 hour, then cooled to 0 OC. Solid sodium bicarbonate (9 g) was added, and the mixture was stirred for 30 minutes. The solution was diluted with ether (350 mL) and water (200 mL), and the phases were separated. The organic phase was washed with water and brine, then dried over MgSO4. The solvent was removed, and the residue was purified by chromatography on silica gel, eluting with 1% methanol/dichloromethane containing 1% NH40H to give the title compound (12.3 g).

H. Res. MS 799.4962 (M+H) Example 179 Compound of Formula (VII): W is absent: R is H: R is is H: Re is methoxv: Rf is H: R is H: R is propyl 35 To a sample of the title compound of Example 178 (150 mg) in methanol (3 mL) was added 10% Pd/C (120 mg), and the mixture was treated with 1 atm of hydrogen at room temperature for 5.5 hours. The catalyst and the solvent were removed, and the 121 SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 residue was purified by chromatography on silica gel, eluting with 1% methanol/dichloromethane containing 1% NH 4 0H to give the title compound (84 mg).

H. Res. MS 801.5110 (M+H) Example 180 Compound of Formula (VII: W is absent: Rh is H: R is H Rd i R_ is methoxy: Rf is H: R is H: R is -C-C(O-H A sample of the title compound (6 g) from Example 178 was treated with ozone according to the procedure of Example 8b to give the title compound (4.5 g).

Example 181 Compound of Formula (VII): W is absent: Rh i s H i Rd isj H R is methoxv: Rfis H: R is H: R is -CH-C=N-O-CH2-phenyl To a sample of the title compound (200 mg) from Example 180 in methanol (1 mL) was added a solution of O-benzylhydroxylamine hydrochloride (76 mg) in methanol (1 mL) and 0.082 mL of N-methylmorpholine. The mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate, washed with water and brine, and dried over MgSO4.

The solvent was removed, and the residue was purified by chromatography on silica gel, eluting with 1% methanol/dichloromethane containing 1% NH 4 0H to give the title compound (125 mg, 56%) as a mixture of syn/anti isomers. H. Res. MS 906.5314 Example 182 Compound of Formula W is absent Rs H R b is H Ris H

R

e is methoxy; Rf is H Rg is H: R is -CH-CH-NH-CH-phen l To a sample of the title compound (150 mg) from Example 180 in methanol (2 mL) at 0 oC was added benzylamine (0.024 mL), acetic acid (0.034 mL) and sodium cyanoborohydride (82 mg, in three portions). The mixture was stirred at room temperature for 2 hours, then quenched by addition of 5% aqueous sodium bicarbonate and extracted into ethyl acetate. The organic phase was washed with water and brine, and dried over MgSO4. The solvent was removed, and the residue was purified by chromatography on silica gel, eluting with 2% methanol/dichloromethane containing 1% NH 4 0H to give the title compound (35 mg). H. Res. MS 892.5526 -122- SUBSTITUTE SHEET (RULE 26) 4 PCT/US97/07 7 0 2 WO 97/42206 Example 183 Co ound of formula X=O R=Phen ro A sample of the compound prepared according to Example 17 (70 mg) was catalytically hydrogenated by procedures described in Example 2. The crude product (64 mg) was purified by column chromatography on silica gel eluting with 98:1:1 dichloromethane/methanoVammonium hydroxide toafford the title compound (44 mg, 44 MS m/z 852 (M+H) Example 184 0 CH(CH=CH-meth hen 1compund of fou X=O Ris CHCH=CH(44methvI henvl) To a mixture of NaH 19 mg) in THF (2 mLe) at 0 C was added tris(4methylphenyl)phosphonium chloride (172 mg) over 3 minutes. The mixture was stirred at ambient temperature for 40 minutes, then re-ecooled to 0 OC. To this mixture was added a THF solution (2 mL) containing a sample of the compound of Example 8 (300 mg). The reaction was sealed under nitrogen and stirred at ambient temperature for 30 hours. The reaction mixture as taken up in EtOAc and washed successively with water, aqueous sodium bicarbonate and brine. The organic layers were dried over MgSO4 and concentrated in vacuo. The crude product (428 mg) was purified by column chromatography on silica gel eluting with 8% methanol in dichloromethane to afford the title compound (120 mg, High Res. MS: Calculated m/z for (M+H)

C

47

H

7 gNO13: 864.5473; Found: 864.5444.

Example 185 Comnound of formula X=O R is -CH -CH(OH)-Pheny To a solution of the compound of Example 8 (500 mg) in T-F (15 mL) at -10 OC was added phenylmagnesium bromide (6.6 mL, 1 molar solution in THF) over 20 minutes under a nitrogen atmosphere. The reaction was stirred at ambient temperature for 2 hours, then cooled to 0C. Water (1 mL) was added, the mixture was stirred for 3 minutes, then extracted with EtOAc. The organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Chromatography on silica gel eluting with dichloromethane/MeOWammonium hydroxide (98:1:1) gave the title compound (300 mg).

High Res. MS: calculated m/z for (M+H)

C

45

H

7 6NO14: 854.5266; Found: 854.5264.

Example 186 Com ound of formula X=O R is -CH-CHBr-CHB To a solution of the compound of Example D (200 mg) in dichloromethane (5 mL) 0 oC was added acetic acid (0.073 mL) and pyridinium bromide perbromide (134 mg).

-123- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 After 1 hour at 0 o the reaction was warmed to ambient temperature and stirred for 16 hours.

The reaction mixture was concentrated in vacuo, the residue was dissolved in EtOAc which was washed with water (2X) and brine, then dried over MgSO4 and concentrated in vacuo.

Chromatography on silica gel eluting with 8% MeOH in dichloromethane gave 155 mg of the title compound. High resolution Mass Spec: calculated m/z for

C

40

H

72 NO13 79 Br2:932.3 3 7 0; Found: 932.3376.

Example 187 ompound of formula X=O. R is -CHCHNHCCH2HCH2-Phenyl To a solution of the compound of Example 8 (150 mg) and 3-phenylpropylamine (0.033 mL) in ethanol (2 mL) was added acetic acid (0.044 mL). After stirring at ambient temperature for 30 minutes, Pd/C (10 125 mg) was added under a nitrogen atmosphere.

The reaction was stirred for 16 hours under 1 atm hydrogen, then the mixture was filtered and concentrated. The residue was dissolved in EtOAc and washed with 5% sodium bicarbonate and brine. After drying over MgSO4 and concentrating in vacuo, the crude residue was purified with column chromatography on silica gel eluting with dichloromethane/MeOH/ammonium hydroxide (97:2:1) to afford of the title compound mg, High resolution Mass Spec: calculated m/z for

C

4 8

H

8 3N2013:895.

5 89 5; Found: 895.5905.

Example 188 Compound f frmula X= R -CH HNHCH(CHPhenyl)CO Me To a solution of the compound of Example 8 (150 mg), L-phenylalanine methyl ester hydrochloride (250 mg), acetic acid (0.066 mL) in methanol (2 mL) was added sodium cyanoborohydride (120 mg in 3 portions) over 5 minutes under nitrogen. The reaction was stirred at ambient temperature for 4.5 hours, then was quenched with aqueous 5% sodium bicarbonate. Following an EtOAc extraction and brine wash, the organic layer was dried over MgSO4. The EtOAc extracts were filtered and concentrated in vacuo. Purification was performed with column chromatography on silica gel eluting with dichloromethane/methanol/ammonium hydroxide (98:1:1) to give the title compound (127 mg, High resolution Mass Spec: calculated m/z for

C

49 H83N2015: 939.5793; Found: 939.5798.

t -124- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 Example 189 Compound of formula X=O. R is -CH2CH2NHCH CH 3CH3 The title compound was prepared by procedures described in Example 187 except substituting propylamine for phenylpropylamine to give the title compound (90 mg, 57%).

H. Res. MS 819.5583 Example 190 Compound of formula X=O. R is .CHCHHNHCH2CO2CH2CH? The title compound was prepared by procedures described in Example 187 except substituting glycine ethyl ester for phenylpropylamine to give the title compound (72 mg, H. Res. MS 863.5472 Example 191 Compound of formula X=O, R is -CH2CHNHCHCH2-Phenyl The title compound was prepared by procedures described in Example 187 except substituting phenethylamine for phenylpropylamine to give of the title compound (55 mg, H. Res. MS 881.5762

(M+H)

Example 192 Compound of formula X=O. R is -CH2CHNHCH2CH2-(4-hydroxyvphenyl) The title compound was prepared by procedures described in Example 187 except substituting 4-hydroxyphenethylamine for phenylpropylamine to give of the title compound mg, H. Res. MS 897.5674

(M+H)

Example 193 Compound of formula X=O R is -CH2CH2NHCHCH-(3-hydroxvhenYl) The title compound was prepared by procedures described in Example 187 except substituting 3-hydroxyphenethylamine for phenylpropylamine to give the title compound (69 mg, MS 897 Example 194 Compound of formula X=O. R is -CH2CHNHCH2CH2-(3-methoxyphenyl The title compound was prepared by procedures described in Example 187 except substituting 3-methoxyphenethylamine for phenylpropylamine to give the title compound (76 mg, H. Res. MS 911.5829 125- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCTIUS97/07702 0 Example 195 Copound of formula X=O R is -CH2CHNH-(2-meth enl The title compound was prepared by procedures described in Example 187 except substituting 2-methoxyphenethylamine for phenylpropylamine to give the title compound 5 (36 mg, H. Res. MS 911.5833 Example 196 Compound of formula X=O. R is -CH2CH2NHCH2H2-(4-methoxyphenyl) The title compound was prepared by procedures described in Example 187 except substituting 4-methoxyphenethylamine for phenylpropylamine to give the title compound (78 mg, H. Res. MS Example 197 Compound of formula X=O. R is -CH2CHNHCH-phenyl The title compound was prepared by procedures described in Example 188 except substituting benzyl amine for L-phenylalanine methyl ester hydrochloride to give the title compound (64 mg, H. Res. MS 911.5833 Example 198 Compound of Formula X is =N-O-(1-isopropoxvcvclohexl) R is fluoromethyl Step 198a. Compound of Formula (XII): X is =N-0-(l-isopropoxvycclohexvl). R is fluoromethyl. RP is Trimethvlsilvl To a 0 OC solution of 15 g of the compound of Formula XII where X is =N-O-(1-isopropoxycyclohexyl) and RP is trimethylsilyl in 150 mL of DMSO and 150 mL of THF was added 113.1 g of bromofluoromethane. A solution of potassium t-butoxide (1 M in THF, 25.4 mL) was added dropwise over 6 hours. The reaction was quenched by addition of allyl amine with stirring for 10 minutes, followed by dilution with water. Ethyl acetate was added, and the organic layer was separated and washed with water and brine, then dried over MgSO4, filtered and concentrated in vacuo to afford 16.5 g of title compound.

Step 198b. Compound of Formula (XII: X is =N-O-(1-isopropoxvcyclohexvl), R is fluoromethvl. RE isH To a room temperature solution of 14.5 g of the compound resulting from step xxxx in 150 mL of anhydrous THF was added 41 mL of 1 M tetrabutylammonium fluoride.

-126- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 After two hours, the solvent was removed under reduced pressure and the residue was dried to constant weight. Purification by column chromatography eluting with 2% methanol in dichloromethane containing 1% ammonium hydroxide afforded 10.24 g of the title compound.

Example 199 Compound of formula X=O. R is -CHCHNHCH2CH9-(3-chlorophenyl) The title compound was prepared by procedures described in Example 188 except substituting 3-chlorophenethylamine for L-phenylalanine methyl ester hydrochloride to give the title compound (94 mg, H. Res. MS 915.5320 Example 200 Compound of formula X=O. R is -CHoCH2NHCH2CH-(2-chlorophenyl) The title compound was prepared by procedures described in Example 188 except substituting 2-chlorophenethylamine for L-phenylalanine methyl ester hydrochloride to give the title compound (88 mg, H. Res. MS 915.5340 Example 201 Compound of formula X=O, R is -CHCH2NHCH2CH?-(4-chlorophenyl) The title compound was prepared by procedures described in Example 188 except substituting 4-chlorophenethylamine for L-phenylalanine methyl ester hydrochloride to give the title compound (84 mg, H. Res. MS 915.5338 (M+H) Example 202 Compound of formula X=O. R is -CH2CH2NHCH2CH2-O-phenyl) The title compound was prepared by procedures described in Example 188 except substituting 2-phenoxyethylamine for L-phenylalanine methyl ester hydrochloride to give the title compound (71 mg, H. Res. MS 897.5654 Example 203 Compound of formula X=O, R is -CHCH2NHCHCHCH2-(4-quinolinYl) The title compound was prepared by procedures described in Example 188 except substituting 4-(propylamino)quinoline for L-phenylalanine methyl ester hydrochloride to give the title compound (60 mg, H. Res. MS 946.5967 (M+H) 127 SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 Example 204 Compound of formula X=O. R is -CHCH2NHCHCH2CH2-(3-uinolinyl) The title compound was prepared by procedures described in Example 188 except substituting 3-(propylamino)quinoline for L-phenylalanine methyl ester hydrochloride to give the title compound. H. Res. MS 946.6022 Example 205 Compound of formula X=0, R is -CH2CHNHCCH.CH2CHCH-phenvy The title compound was prepared by procedures described in Example 188 except substituting 4-phenylbutylamine for L-phenylalanine methyl ester hydrochloride to give the title compound. H. Res. MS 909.6046 Example 206 Compound of formula X=0. R is -CH?-CH=N-NH-C(O)-NH? The title compound was prepared by procedures described in Example 18 except substituting semicarbazide hydrochloride for methoxylamine hydrochloride to give the title compound as a 10:1 anti/syn mixture of isomers. H. Res. MS 833.5153 Example 207 Compound of formula X=O. R is -CH2-CH=N-NH-(2-pyridinl) The title compound was prepared by procedures described in Example 18 except substituting 2-hydrazinopyridine for methoxylamine hydrochloride to give the title compound as a 1:1 anti/syn mixture of isomers. H. Res. MS 867.5351 Example 208 Compound of formula X=O. R is -CH?-CH=N-(4-methvlpiperazinyl) The title compound was prepared by procedures described in Example 18 except substituting 1-amino-4-methylpiperazine for methoxylamine hydrochloride to give the title compound as a trans isomer. H. Res. MS 873.5765 Example 209 Compound of formula X=O. R is -CHq-CH=N-O-phenvl The title compound was prepared by procedures described in Example 18 except substituting O-phenylhydroxylamine hydrochloride for methoxylamine hydrochloride to give the title compound as a 1:1 anti/syn mixture of isomers. H. Res. MS 867.5198 128- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 Example 210 Compound of formula X=O. R is -CH2CH(OH)CH2NHCHCH,-phenyl To a solution of the compound from Example 4 (200 mg) in DMF (1 mL) was added benzylamine (0.160 mL), and the reaction was heated at 65 oC for 20 hours. The mixture 5 was diluted with EtOAC (30 mL) and washed successively with water, 5% sodium bicarbonate and brine. The EtOAc layers were then dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/ammonium hydroxide (96:3:1) to afford of the title compound (109 mg) as a mixture of diastereomers. H. Res. MS 911.5853 Example 211 Compound of formula X=O, R is -CH2CH(OH)CH2NHCH?-(4-pvridinvl The title compound was prepared by procedures described in Example 210 except substituting 4-(aminoethyl)pyridine for benzylamine to give the title compound (50 mg, H. Res. MS 898.5635 Example 212 Compound of Formula (VII): W is absent: Rh is H: R is H Rd is H:

R

e is methoxv: Rf is H: Rg is H: R is -CH2-C=N-O-H (anti-isomer) The title compound was prepared by procedures described in Example 181 substituting hydroxylamine hydrochloride for O-benzylhydroxylamine hydrochloride. The crude product was obtained as a mixture of syn/anti isomers. After chromatography on silica gel eluting with dichloromethane/methanol/ammonium hydroxide (96:3:1) the title compound was obtained as a single anti isomer. H. Res. MS 816.4835 (M+H) Example 213 Compound of Formula (VII): W is absent: R is H: R is H: Rd is H R9 is methoxv: Rf is H: Rg is H: R is -CH2-C=N-O-H (svn-isomer) After chromatography of the mixture of syn and anti isomers from Example 212 on silica gel eluting with dichloromethane/methanol/ammonium hydroxide (96:3:1) the title compound was obtained as a single syn isomer. H. Res. MS 816.4835 -129- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 ExaMple 214 Compound of Formula (VII): W is absent: Rl2JisHRP- i -Rlis H.

Rt is methoxy: Rfis H: RE. is H: R is -CH97-C=N-O-p~henvl The title compound was prepared by procedures described in Example 181 substituting 0-phenyihydroxylamine hydrochloride for O-benzylhydroxylamine hydrochloride. The title compound was obtained as a mixture of syn/anti isomers. H. Res.

MS 892.5151 Example 215 Compound of Formula (VII): W is absent: R is H, R9 i H:Rd is H: R-Q is methoxy: Rf is .9 is H; R is -CH?-C=N-O-CH-(4-nitrophenYl) The title compound was prepared by procedures described in Example 181 substituting O-( 4 -nitrobenzyl)hydroxylamfine hydrochloride for O-benzylhydroxylamine hydrochloride. The title compound was obtained as a mixture of syn/anti isomers. H. Res.

MS 951.5197 Example 216 Compound of Formula VII: W is absent: R is H: RIQji;Rd i H R9 is methoxy: Rf is H R9 is H: R is -CH-C=N-O-CH?-(4-guinolinvl) To a solution of 130 mgs of the title compound of Example 180 in 2 mL MeOH was added 100 mg O-( 4 -quinolyl)hydroxylam-ine and catalytic p-toluenesulfonic acid. The reaction was heated at 60 0 C for 16 hours. The reaction was concentrated in vacuc. The residue obtained was chromatographed on silica gel eluting with dichloromethane/methanollarnmorium hydroxide (98: 1: 1) to afford 85 mg of the title compound as a mixture of syn/anti isomers. H. Res. MS 957.5443 Example 217 Compound of Formula (VII): W is absent: hi H I is H: R- is H: R-1 is methoxy: Rf is H;RP. is H: R is -CH-C=N--C(Rheavl)a The title compound was prepared by procedures described in Example 216 except substituting 0-tritylhydroxylamidne for O-( 4 -quinolyl)hydroxylamidne. The title compound was obtained as a mixture of syn/anti isomers. MS 1058 -130- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 Example 218 Compound of Formula (VII): W is absent: Ris H: R is H: Rd is H Rp is methoxv: Rf is H: R is H: R is -CH7-CH2-NH? A 150 mg sample of the title compound from Example 180 was dissolved in 2 mL of dichloromethane and 24 microliters of benzylamine and 50 mg MgSO4 were added. The reaction was stirred at ambient tremperature for 16 hours, filtered and concentrated in vacuo.

The residue obtained was dissolved in EtOH and 120 mg 10% Pd/C was added under a nitrogen atmosphere. The reaction was then placed under 1 atm hydrogen and stirred for 16 hours. The reaction was filtered and concentrated in vacuo. The residue obtained was purified with column chromatography on silica gel eluting with dichloromethane/MeOH/ammonium hydroxide (97:2:1) to afford 40 mg of the title compound. MS 802 Example 219 Compound of Formula (VII): W is absent: Rh is H R is H: R is

H

R£ is methoxy: Rf is H: Rg is H: R is -CH-CH-NH-CH2-phenyl To a solution of 150 mg of the title compound from Example 180, 24 microliters of benzylamine and 34 microliters of acetic acid in 2 mL of MeOH was added 82 mg sodium cyanoborohydride in 3 portions over 5 minutes under a nitrogen atmosphere. The reaction was stirred at ambient temperature for 4.5 hours and was quenched with aqueous sodium bicarbonate. Following an EtOAc extraction and brine wash the organic layer was dried over MgSO4. The EtOAc extracts were filtered and concentrated in vacuo.

Purification was performed with column chromatography on silica gel eluting with dichloromethane/methanol/ammonium hydroxide (97:2:1) to give 35 mg of the title compound. H. Res. MS 892.5526 (M+H) Example 220 Compound of Formula (VII): W is absent; Rh is HR is H R is methoxv: Rf is is H R R is -CH-CH-NH-CH2-CH2-phenyl A 200 mg sample of the title compound from Example 180 was dissolved in 2 mL of dichloromethane, and 36 microliters of phenethylamine and 50 mgs of MgSO4 were added.

The reaction was stirred at ambient tremperature for 16 hours, then filtered and concentrated in vacuo. The residue obtained was dissolved in EtOH, and 150 mg 10% Pd/C was added under a nitrogen atmosphere. The reaction was then placed under 1 atm hydrogen and stirred for 20 hours. The reaction mixture was filtered and concentrated in vacuo, and the residue obtained was purified with column chromatography on silica gel eluting with 131 SUBSTITUTE SHEET (RULE 26) 1 PCT/US97/07702 WO 97/42206 Sdichloromethane/MeO/ammoium hydroxide (97:2:1) to afford 104 mg of the title compound. H. Res. MS 906.5713 Example 221 Compound of Formula NVW: W is absent-: s R is methoxv Rf is H RY is H R is -CH-C N H The title compound was prepared by the procedures described in Example 220 except substituting phenylpropylamine for phenethylamine. H. Res. MS 920.5863 Example 222 Co ound of Formula X is R is (3-iodohenl meth1 S 222a. Comound of Formula X is is otrooxcvclohexvl R is (3iodophenvlmethvl. R is Trimethylsilvl To a 0 OC solution flushed with nitrogen of 33.5 g (0.032 mmol) of the compound of Formula XII where X is =N-O-(-isopropoxycyclhexyl) and RP is trimethylsilyl in 120 mL of DMSO and 120 mL of THF was added 24 g (0.081 mmol) of 3-iodobenzyl bromide over 10 minutes. A solution of potassium t-butoxide (1 M in THF, 65 mL, 0.065 mmol) was added at 0 °C over 6 hours. The reaction was stirred for an additional hour, then taken up inn ethyl acetate. The organic layer was separated, washed with water and brine, then dried over MgSO4, filtered and concentrated in vacuo to afford 4( g of title compound

MS

1249 Step 222b. Com und of Formula X is IN-isro ox lohe 1 R s Siodo henylimethyv, Rm is H The compound from step 222a was suspended in acetonitrile (130 mL). and water mL) and acetic acid (65 mL) were added to provide a clear solution. The reaction mixture was stirred at room temperature for 20 hours, and the solvent was removed under reduced pressureto give the title compound (32 MS 965 (M+H) S 222c. Comound of mula X is R is (3-iodo henylmeth The compound from step 222b (32 g, 0.032 mol) in 500 mL of 1:1 EtOH-water was treated with NaHSO3 (67.39 g, 0.65 mol) and formic acid (6.11 mL) and warmed at ingC under nitrogen for 1 hour. The ethanol was removed under vacuum, and the resultng solution was adjusted to pH 10 with sodium carbonate (27.5 g, 0.259 mol) and extracted with EtOAc. The organic phase waswashed with water and brine dried over MgSO 4 -132- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 filtered and concentrated in vacuo. The crude material (9.1 g) was purified by column chromatography eluting with 1% MeOH in dichloromethane containing 1% ammonium hydroxide to give the pure title compound. MS 950 Example 223 Compound of Formula X is R is (4-fluorophenvl)methyl Following the procedures of Example 222, except substituting 4-fluorobenzyl bromide for the 3-iodobenzyl bromide thereof, the title compound was prepared. MS 842 Example 224 Compound of Formula X is R is -CH?-CH=CH?-(3-quinolinyl) To a sample of the compound from Example 1 (3.09 g, 4 mmol) in acetonitrile mL) were added 3-bromoquinoline (1.08 mL, 8.0 mmol), palladium acetate (180 mg, 0.8 mmol), tri-(o-tolyl)phosphine (365 mg, 1.2 mmol) and triethylamine (1.40 mL, 10 mmol).

The mixture was degassed by bubbling N 2 through it for 30 minutes, sealed in a tube under nitrogen, and heated at 60 °C for 1 hour and at 100 oC for 14 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was separated, washed with saturated NaHCO3 and brine, and dried over MgSO4. The solvent was removed to give crude product which was purified by chromatography on silica gel, eluting with 40-60% acetone/hexane to give the title compound (2.73g). MS 901 Example 225 Compound of Formula X is Rh i is HR d is acetyvl R is methox;: Rf i acetvl: R is -CH-CHCH=CH To a solution of the compound of Example 1 (80 g, 103 mmol and DMAP (4.0 g, 32.7 mmol) in dichloromethane (200 mL) was added acetic anhydride (40 mL, 400 mmol).

The solution was stirred for 5 hours at ambient temperature. The mixture was diluted with dichloromethane (800 mL). The organic phase was washed with 5% Na 2 CO3, saturated NaHCO3 and brine and dried over MgSO4. The solvent was removed under vacuum, and the residue was dried. The residue was crystallized from acetonitrile to give the title compound (60.0 g).

Example 226 Compound of Formula (VII): W is absent: R isis i HR Rd is acetvyl R e is methoxy; Rf is acetvl: Rg is H: R is -CH2-CH=CH2 -133- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 Step 226a. (Compound (28) of Scheme V: 2'-RP-is acel: 4"-RE is acetyl; R is allyl To a solution of the compound of Example 225 (19.5 g, 22.75 mmol) in THF (125 mL) cooled to -48 OC in a dry ice-acetonitrile bath was added sodium bis(trimethylsilyl)amide (30.0 mL, 1 M in THF, 30.0 mmol) over 30 min. After 45 min, a solution of 15.0 g (91.0 mmol) of carbonyldiimidazole in 75 mL of THF and 50 mL of DMF was added. The mixture was stirred for 2.5 hrs at -48 'C and 18 hrs at room temperature. The reaction was quenched by adding a solution of 0.5 M NaH2PO4 (200 mL). The product was isolated by extraction of the reaction mixture with ethyl acetate. The extract was dried with MgSO4 and concentrated to give the crude product, which was purified by flash chromatography using 40-60% acetone/hexanes, yielding 19.66 g (92%) of the title compound.

Step 226b. Compound (29) of Scheme V--which is also a Compound of Formula (VII): W is absent Rh is H: Rd R is acetyl: R is methox: is acetl i H: R is -CH?-CH=CH2 To a solution of compound from step 226a (40.0 g, 42.9 mmol) in acetonitrile (1000 mL) and THF (100 mL) was added concentrated ammonium hydroxide (28-30%, 120 mL).

The mixture was stirred at room temperature for 7 days. Solvents were removed in vacuo, and the residue was taked up in ethyl acetate. The organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/MeOH/ammonium hydroxide (10:1:0.05) to give the title compound (23.07 HRMS: calculated m/z for C45H74N2015: 883.5164; Found: 883.5162.

Example 227 Compound of Formula (VII: W is absent: Rh is H: R i H: is acetl: R is methoxy Rf is acetvl: Ris H: R is -CH-CH=CH-(3-quinolinvl) To a sample of the title compound from Example 226 (20.5 g, 23.2 mmol) in acetonitrile (200 mL) were added 3-bromoquinoline (6.47 mL, 31.1 mmol), palladium acetate (1.07 g, 4.76 mmol), tri-(o-tolyl)phosphine (2.43 g, 7.97 mmol) and triethylamine (9.13 mL, 65.5 mmol). The mixture was degassed by bubbling N 2 through for minutes, sealed in a tube under nitrogen, and heated at 60 °C for 1 hour and 14 hours at 100 The mixture was cooled and diluted with ethyl acetate, which was separated and washed with saturated NaHCO3 and brine, then dried over MgSO4. The solvents were removed and the crude product was purified by chromatography on silica gel eluting with 40-60% acetone/hexane to give the title compound (21.0 MS: at m/z 883.

-134- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 Example 228 Compound of Formula (VII): W is absent Rh is H RisHRd is acetvl; R ,is methoxv: R f is H: R is H R is -CH2CH=CH2-(3-quinolinyl) A sample of compound from Example 227 (109 mg, 0.108 mmol) in MeOH (3 mL) was heated at reflux for 4 hours. The solvent was removed by evaporation, and the crude product was purified by chromatography on silica gel with dichloromethane/MeOH/ammonium hydroxide (10:1:0.05) to give the title compound mg). HRMS: calculated m/z for

C

52

H

78 N3014: 968.5484; Found: 968.5485.

Example 229 Compound of Formula (VII: W is absent: Rh is H. Ris H Rd is H Re is methoxyv Rf is H; Rg R is -HCHCH,-(3-quinolinvY A sample of compound from Example 228 (2.53 g, 2.51 mmol) from above in MeOH (50 mL) was added 7.5 mL 2 N NaOH. The mixture was stirred at room temperature for 24 hours before it was diluted with ethyl acetate. The organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Chromatography on silica gel eluting with dichloromethane/MeOH/ammonium hydroxide (10:1:0.05) gave the title compound (1.42 g, H. Res. MS 926.5396.

Example 230 Compound of Formula (VII: W is absent: Rbhis HR is RH: d is H R. is methoxvy Rf is acetvl: Re is H: R is -CH CH=CH-(3-quinolinyl) A sample of compound from Example 227 (1.42 g, 1.53 mmol) in dichloromethane mL) was treated with triethylamine (0.25 mL, 1.79 mmol) and acetic anhydride (0.29 mL, 2.12 mmol) at room temperature for 12 hours. The mixture was washed with a saturated solution of NaHCO3, dried over MgSO4, and concentrated in vacuo. Crude product was further purifed by recrystalization from hot acetonitrile to give 1.40 g of the title compound.

Example 231 Compound of Formula (VII): W is absent Rh is Hi Ris Ris methoxyv

R

e is methoxy: Rfs is H: R is -CHCH=CH?-(3-quinolinyl) A sample of compound from Example 230 O0.1g, 0.103 mmol) in THF (2 mL) at 8 OC was added NaN(TMS)2 (1 M in THF, 0.19 mL). After 30 min, iodomethane (0.027 g, 0.189 mmol) was added. After stirred at room temperature for 12 hours,the mixture was -135- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/0770 2 diluted with AcOEt. Organic layers were washed with water, brine, and dried over Na2SO4, concentrated in vacuo to give crude product. This material was then dissolved in methanol (3 mL) and heated at reflux for 4 hours. Solvent was removed by evaporation i vacuo, residue was purified by chromatography on silica gel eluted with 95:5:1 dichloromethane:MeOH:NH 4 0H to give title compound.

Example 232 Compound of Formula (VII): W is absent; Rh is H Ris H: R e is methoxyv R is ethenslfonvloxvR is acetyl Ris H: R is -CH2CH=CH?-(3-quinolinyl) A sample of compound from Example 231 (0.49 g, 0.51 mmol) was dissolved in pyridine (15 mL) and cooled to 0 OC. 2-Chloroethanesulfonyl chloride (0.262 g, 1.61 mmol) was added dropwise, the mixture was stirred at 8 OC for 15 minutes and at room temperature for 48 hours. The mixture was diluted with AcOEt, and washed with NaHCO3. The aqueous phase was extracted with AcOEt, and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentraded in vacuo. The crude product was purified by flash chromatography with 95:5:1 dichloromethane:MeOH:NH 4 0H to give 0.28 g title compound as a yellow foam.

Example 233 Compound of Formula (VII): W is absent: R h is H; R is HR is methoxy R is 2(dimethvlamino)ethlsulfonvloxv: Rf is ace is H R is -CHCH=CH-(3quinolinvl) To a sample of compound from Example 232 (70 mg, 0.066 mmol) in CH 3 CN (3 mL) was added dimethylamine (2 M in THF, 0.4 mL, 0.079 mmol), and the mixture was stirred for 12 hours at room temperature. The mixture was evaporated to dryness, and the residue was dissolved in 5 mL MeOH and heated at reflux for 4 hours. The solvent was removed by evaporation, and the crude product was purified by chromatography on silica gel with dichloromethane/MeOH/ammonium hydroxide (20:1:0.05) to give the title compound (32 mg). MS m/z 1061 [M+H] Example 234 Compound of Formula (VII): W is absentl Rhj isH Rj R is methox R is 2-(henlthioethox Ris acetl: R is H R is -CH2CH=CH-(3-uinolinyl) Following the procedure of Example 233, except substituting thiophenol for the 35 dimethylamine thereof, the title compound was prepared (25 mg).

-136- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702 Example 235 Compound of Formula (VII): W is absent Rb is H R£ and Re taken together is =0; Re is methoxy R is H: Rg is H: R is -CH2CH=CH2-(3-quinolinyl) To a solution of N-chlorosuccinimide (110.5 mg, 0.827 mmol) in dichlomethane (3 mL) was added dimethylsulfide (64.3 mg, 1.03 mmol) at -18 OC. After 10 min, a solution of compound from Example 231 (400 mg, 0.414 mmol) in dichlomethane (3 mL) was added. The mixture was stirred at -10 OC to 0 OC for 45 minutes and triethylamine (144 mL, 1.03 mmol) was added. The mixture was diluted with dichlomethane (10 mL), washed with NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo to give 400 mg of the 2'acetyl compound. A 40 mg sample of this material was heated in refluxing MeOH (3 mL) for 3 hours. Methanol was evaporated, and the residue was purified by chromatography on silica gel eluting with dichloromethane/MeOH/ammonium hydroxide (20:1:0.05) to give the title compound (32 mg). MS: at m/z 924.

Example 236 Compound of Formula (VII): W is absent: is Hi: RsHRd is methoxy: Re is (2-nitroDhenvl)aminocarbonvloxy R is H; R is H: R is -CH2CH=CH2-(3quinolinvl) A sample of the compound from Example 231 (50 mg, 0.054 mmol), 2nitrophenylisocyanate (13 mg, 0.081 mmol) and DAMP (7.0 mg, 0.057 mmol) in toluene (2 mL) was heated at 108 OC for 3 hrs. After 5 mL MeOH was added, the mixture was heated at reflux for 4 hours. Solvents were removed in vacuo, and the residue was purified by flash chromatography on silica gel eluted withdichloromethane/MeOH/ammonium hydroxide (20:1:0.05) to give the title compound, 38mg. MS: at m/z 1090.

Examples 237-283 Using the procedures described in the preceeding examples and schemes and methods known in the synthetic organic chemistry art, the following compounds having the formula wherein R is as described below can be prepared.

137 SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCTIUS97/07702 'OH 3

(X)

Ex. No. Structure of R 237

O

238 ~Y OH 239 H 240 H C H 3 241 OH 3

OH

3 2420 243 NH 2 138 SUBSTITUTE SHEET (RULE 26) i) V WO 97/42206 PCTIUS97/07702 0 244 0 N N NH 2

H

245 0 Nk CH 3

H

246 0, CH 3 247 CH 3 248 OH 3

OH

3 249 CH3 '11-

CH

3 250 C 3 251 252 253 CH 3 254 255 -139- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PTU9/70 PCT/US97/07702 256

~CH

3 257CH 258

OH

3 259 ooo, N0 2 260 loo. c 2 6 1 O

H

264CH 3 265

OH

3 266

H

-140- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCTIUS97/07702 267 268 269

CH

3 270 271 272

N

IN

273 274 275 N02

NO

2 SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCT/US97/07702

I

276 277 278 279 280 'Y OCH 3 0 o, c

H

3 ,Y NH 2 0 j,, 0 -NK

CH

3 281

NCI

282 283 0 0 -0Br Examples 284-315 Using the procedures described in the preceeding examples and schemes and methods known in the synthetic organic chemistry art, the following compounds can be prepared. The macrolide ring systems are selected from the group consisting of: -142- SUBSTITUTE SHEET (RULE 26)

V

WO 97/42206 PCTIUS97/07702 -143- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCTfUS97/07702 Rg wherein A, B, D, E, W, X, Y, Z, R, Ra, Rb, Rc, Rd, Re, Rf. Rg and Rb are as previously defined.

-144- WO 97/42206 PCT/US97/0770 2 145 WO 97/42206 PCT1US97/07702 294 Crotyl bromide

H

295 1 -Bromo-2-pentene C H 3 296 3 -Bromo-l1-propenyl Phenyl sulfone 0 297 3-Bromo- 1trimethylsilyl- 1 -propync 298 j 3 -Bromo-2-octyne 299 I-Bromo-2-butyne 300 2-Picolyl chloride

CH

3

OH

3 No 301 3-Picolyl chloride 302 4 -Picolyl chloride -146- WO 97/42206 303 PCT1US97/07702 4 -Bromomethyl quinolineI

SN

304 Bromoacetontrjjle 305 Epichiorohydrin 306 Bromofluoromethane 307 Bromonitromeffiane

N

0 308 Methyl bromoacetate 309 Methoxymethyl chloride 311 2 -Bromoacetophenone 312 1 -Bromo-2-butanone 313 Bromo chioromethane 0 0

H

N2 0

-NK%%CH

3 0 ~NC I 147 WO 97/42206 PCT/US97/07702 314 Bromomethyl phenyl sulfone 00 315 1,3-Dibromo- 1-propene

H

Br Example 316 In Vitro Assay of Antibacterial Activity Representative compounds of the present invention were assayed in vitro for antibacterial activity as follows: Twelve petri dishes containing successive aqueous dilutions of the test compound mixed with 10 mL of sterilized Brain Heart Infusion (BHI) agar (Difco 0418-01-5) were prepared. Each plate was inoculated with 1:100 (or 1:10 for slow-growing strains, such as Micrococcus and Streptococcus) dilutions of up to 32 different microorganisms, using a Steers replicator block. The inoculated plates were incubated at 35-37 °C for 20 to 24 hours. In addition, a control plate, using BHI agar containing no test compound, was prepared and incubated at the beginning and end of each test.

An additional plate containing a compound having known susceptibility patterns for the organisms being tested and belonging to the same antibiotic class as the test compound was also prepared and incubated as a further control, as well as to provide test-to-test comparability. Erythromycin A was used for this purpose.

After incubation, each plate was visually inspected. The minimum inhibitory concentration (MIC) was defined as the lowest concentration of drug yielding no growth, a slight haze, or sparsely isolated colonies on the inoculum spot as compared to the growth control. The results of this assay, shown below in Table 4 demonstrate the antibacterial activity of the compounds of the invention.

I'

148- WO 97/42206 PCT/US97/07702 able kA Antibacterial Activity (MIC's) of Selected Compounds Microorganism Staphylococcus aureus ATCC 6538P Staphylococcus aureus A5177 Staphylococcus aureus A-5278 Staphylococcus aureus CMX 642A Staphylococcus aureus NCTC10649M Staphylococcus aureus CMX 553 Staphylococcus aureus 1775 Staphylococcus epidermidis 3519 Enterococcusfaecium ATCC 8043 Streptococcus bovis A-5169 Streptococcus agalactiae CMX 508 Streptococcus pyogenes EES61 Streptococcus pyogenes 930 Streptococcus pyogenes PIU 2548 Micrococcus luteus ATCC 9341 Micrococcus luteus ATCC 4698 Escherichia coli JUHL Escherichia coli SS Escherichia coli DC-2 Escherichia coli H560 Escherichia coli KNK 437 Enterobacter aerogenes ATCC 13048 Klebsiella pneumoniae ATCC 8045 Providencia struartii CMX 640 Pseudomonas aeruginosa

BMHIO

Pseudomonas aeruginosa 5007 Pseudomonas aeruginosa K799/WT Pseudomonas aeruginosa K799/61 Pseudomonas capacia 2961 Actinetobacter calcoaceticus CMX 669 Pseudomonas aeruginosa DPHD-5263 Pseudomonas aeruginosa DPHD-2862 Candida albicans CCH 442 EEY. A 0.2 3.1 >100 0.39 0.39 0.39 >100 0.39 0.05 0.02 0.05 >100 3.1 0.05 0.2 >100 0.78 >100 50 100 >100 >100 >100 >100 >100 100 1.56 >100 12.5 >100 >100 >100 Example lB 0.78 12.5 >100 1.56 3.1 1.56 >100 0.39 0.2 0.02 0.1 >100 6.2 0.2 3.1 >100 3.1 >100 100 >100 >100 >100 >100 >100 >100 >100 6.2 >100 50 >100 >100 >100 Example IC 0.78 12.5 >100 1.56 0.78 0.78 >100 0.39 0.2 0.01 0.01 >100 3.1 0.1 1.56 100 0.78 >100 100 >100 >100 >100 >100 >100 >100 >100 6.2 >100 >100 >100 >100 -149- WO 97/42206 PCT/US97/07702 Mycobacterium smegmatis ATCC 114 Table 2 Antibacterial Activity (MIC's) of Selected Compounds Continued Microorganism Staphylococcus aureus ATCC 6538P Staphylococcus aureus A5177 Staphylococcus aureus A-5278 Staphylococcus aureus CMX 642A Staphylococcus aureus NCTC1649M Staphylococcus aureus CMX 553 Staphylococcus aureus 1775 Staphylococcus epidermidis 3519 Enterococcusfaecium ATCC 8043 Streptococcus bovis A-5169 Streptococcus agalactiae CMX 508 Streptococcus pyogenes EES61 Streptococcuspyogenes 930 Streptococcus pyogenes PIU 2548 Micrococcus luteus ATCC 9341 Micrococcus luteus ATCC 4698 Escherichia coli JUHL Escherichia coli SS Escherichia coli DC-2 Escherichia coli H560 Escherichia coli KNK 437 Enterobacter aerogenes ATCC 13048 Klebsiella pneumoniae ATCC 8045 Providencia struartii CMX 640 Pseudomonas aeruginosa BMHIO Pseudonmonas aeruginosa 5007 Pseudomonas aeruginosa K799/WT Pseudomonas aeruginosa K799/61 Pseudomonas capacia 2961 Actinetobacter calcoaceticus CMX 669 Ely. A 0.2 3.1 >100 0.39 0.39 0.39 >100 0.39 0.05 0.02 0.05 >100 3.1 0.05 0.2 >100 0.78 >100 50 100 >100 >100 >100 >100 >100 100 1.56 >100 12.5 Example 2 3.1 25 >100 12.5 6.2 3.1 >100 1.56 3.1 0.05 0.2 0.05 >100 6.2 0.2 3.1 >100 1.56 >100 >100 >100 >100 >100 >100 >100 >100 6.2 >100 50 >100 Example 3 1.56 >100 1.56 1.56 3.1 >100 0.78 0.39 0.2 0.39 0.2 >100 12.5 0.1 1.56 1.36 100 >100 >100 >100 >100 >100 >100 1.56 >100 12.5 -150- WO 97/42206 0 PCT/US97/07702 Pseudomonas aeruginosa DPHD-5263 Pseudomonas aeruginosa DPHD-2862 Candida albicans CCH 442 Mycobacterium smegmatis ATCC 114 >100 >100 >100 >100 >100 0.1 >100 >100 >100 0.78 Tablek2 Antibacterial Activity (MIC's) of Selected Compounds Continued Microorganism Staphylococcus aureus ATCC 6538P Staphylococcus aureus A5177 Staphylococcus aureus A-5278 Staphylococcus aureus CMX 642A Staphylococcus aureus NCIC10649M Staphylococcus aureus CMX 553 Staphylococcus aureus 1775 Staphylococcus epidermidis 3519 Enterococcusfaecium ATCC 8043 Streptococcus bovis A-5169 Streptococcus agalactiae CMX 508 Streptococcus pyogenes EES61 Streptococcus pyogenes 930 Streptococcus pyogenes PIU 2548 Micrococcus luteus ATCC 9341 Micrococcus luteus ATCC 4698 Escherichia coli JUHL Escherichia coli SS Escherichia coli DC-2 Escherichia coli H560 Escherichia coli KNK 437 Enterobacter aerogenes ATCC 13048 Klebsiella pneumoniae ATCC 8045 Providencia struartii CMX 640 Pseudomonas aeruginosa BMH10O Pseudomonas aeruginosa 5007 Pseudomonas aeruginosa K799/WT Er. A 0.2 3.1 >100 0.39 0.39 0.39 >100 0.39 0.05 0.02 0.05 >100 3.1 0.05 0.2 >100 0.78 >100 50 100 >100 >100 >100 >100 >100 100 Example 5 0.78 12.5 >100 0.78 0.78 0.78 >100 1.56 0.39 0.05 0.1 0.05 >100 0.1 3.1 25 0.78 50 50 50 100 100 >100 100 >100 >100 Example 6 0.78 >100 1.56 0.78 0.78 >100 0.78 0.39 0.1 0.05 >100 6.2 0.1 1.56 >100 0.78 >100 100 >100 >100 >100 >100 >100 >100 >100 151 WO 97/42206 PCT/US97/07702 0 Pseudomonas aeruginosa K799/61 Pseudomonas capacia 2961 Actinetobacter calcoaceticus CMX 669 Pseudomonas aeruginosa DPHD-5263 Pseudomonas aeruginosa DPHD-2862 Candida albicans CCH 442 Mycobacterium smegmatis ATCC 114 1.56 >100 12.5 >100 >100 >100 3.1 1.56 >100 12.5 >100 >100 >100 1.56 12.5 >100 >100 >100 >100 0.2 Table 2 Antibacterial Activity (MIC's) of Selected Compounds Continued Microorganism Staphylococcus aureus ATCC 6538P Staphylococcus aureus A5177 Staphylococcus aureus A-5278 Staphylococcus aureus CMX 642A Staphylococcus aureus NCTC10649M Staphylococcus aureus CMX 553 Staphylococcus aureus 1775 Staphylococcus epidermidis 3519 Enterococcusfaecium ATCC 8043 Streptococcus bovis A-5169 Streptococcus agalactiae CMX 508 Streptococcus pyogenes EES61 Streptococcus pyogenes 930 Streptococcus pyogenes PIU 2548 Micrococcus luteus ATCC 9341 Micrococcus luteus ATCC 4698 Escherichia coli JUHL Escherichia coli SS Escherichia coli DC-2 Escherichia coli H560 Escherichia coli KNK 437 Enterobacter aerogenes ATCC 13048 Klebsiella pneumoniae ATCC 8045 Erv. A 0.2 3.1 >100 0.39 0.39 0.39 >100 0.39 0.05 0.02 0.05 >100 3.1 0.05 0.2 >100 0.78 >100 50 100 >100 >100 Example 7 0.39 3.1 >100 0.39 0.39 0.39 >100 0.39 0.39 0.01 0.01 0.01 >100 0.02 0.78 12.5 0.2 6.2 1.56 12.5 50 25 Example 8 0.78 12.5 >100 0.78 0.78 0.78 >100 0.78 0.39 0.2 0.39 0.1 >100( 0.1 1.56 100 1.56 >100 >100 >100 >100 -152- WO 97/42206 PCT/US97/07702 0 Providencia struartii CMX 640 Pseudomonas aeruginosa BMHIO Pseudomonas aeruginosa 5007 Pseudomonas aeruginosa K799/WT Pseudomonas aeruginosa K799/61 Pseudomonas capacia 2961 Actinetobacter calcoaceticus CMX 669 Pseudomonas aeruginosa DPHD-5263 Pseudomonas aeruginosa DPHD-2862 Candida albicans CCH 442 Mycobacterium smegmatis ATCC 114 >100 >100 >100 100 1.56 >100 12.5 >100 >100 >100 3.1 >100 25 >100 100 0.39 >100 12.5 >100 >100 >100 0.2 >100 >100 >100 >100 3.1 >100 >100 >100 >100 6.2 0.39 Table 2 Antibacterial Activity (MIC's) of Selected Compounds Continued Microorganism Staphylococcus aureus ATCC 6538P Staphylococcus aureus A5177 Staphylococcus aureus A-5278 Staphylococcus aureus CMX 642A Staphylococcus aureus NCTC10649M Staphylococcus aureus CMX 553 Staphylococcus aureus 1775 Staphylococcus epidermidis 3519 Enterococcusfaecium ATCC 8043 Streptococcus bovis A-5169 Streptococcus agalactiae CMX 508 Streptococcus pyogenes EES61 Streptococcus pyogenes 930 Streptococcus pyogenes PIU 2548 Micrococcus luteus ATCC 9341 Micrococcus luteus ATCC 4698 Escherichia coli JUHL Escherichia coli SS Escherichia coli DC-2 Ery A 0.2 3.1 >100 0.39 0.39 0.39 >100 0.39 0.05 0.02 0.05 >100 3.1 0.05 0.2 >100 0.78 >100 Example 9 3.1 >100 3.1 3.1 >100 3.1 3.1 3.1 3.1 >100 12.5 3.1 >100 Example 0.2 6.2 >100 0.39 0.39 0.39 >100 0.2 0.1 0.01 0.05 0.01 >100 0.05 0.78 0.78 100 -153- WO 97/42206 PCT/US97/07702 Escherichia coli H560 Escherichia coli KNK 437 Enterobacter aerogenes ATCC 13048 Klebsiella pneumoniae ATCC 8045 Providencia struartii CMX 640 Pseudomonas aeruginosa BMH10 Pseudomonas aeruginosa 5007 Pseudomonas aeruginosa K799/WT Pseudomonas aeruginosa K799/61 Pseudomonas capacia 2961 Actinetobacter calcoaceticus CMX 669 Pseudomonas aeruginosa DPHD-5263 Pseudomonas aeruginosa DPHD-2862 Candida albicans CCH 442 Mycobacterium smegmatis ATCC 114 Nocarrdia asteroides ATCC 9970 100 >100 >100 >100 >100 >100 100 1.56 >100 12.5 >100 >100 >100 3.1 >100 >100 >100 >100 >100 >100 >100 >100 12.5 >100 50 >100 >100 >100 3.1 >100 >100 >100 >100 100 >100 >100 3.1 >100 12.5 >100 >100 >100 0.39 Table 2 Antibacterial Activity (MIC's) of Selected Compounds Continued Microorganism Staphylococcus aureus ATCC 6538P Staphylococcus aureus A5177 Staphylococcus aureus A-5278 Staphylococcus aureus CMX 642A Staphylococcus aureus NCTC10649M Staphylococcus aureus CMX 553 Staphylococcus aureus 1775 Staphylococcus epidermidis 3519 Enterococcusfaecium ATCC 8043 Streptococcus bovis A-5169 Streptococcus agalactiae CMX 508 Streptococcus pyogenes EES61 Streptococcuspyogenes 930 Streptococcus pyogenes PIU 2548 Ery. A 0.2 3.1 >100 0.39 0.39 0.39 >100 0.39 0.05 0.02 0.05 >100 3.1 Example 11 0.78 6.2 >100 1.56 0.78 0.78 >100 0.78 0.39 0.2 0.05 0.05 >100 25 Example 12 0.39 >100 0.39 0.39 0.39 >100 0.39 0.1 0.05 0.05 0.05 >100 12.5 -154- WO 97/42206 PCT/S97/0772 WO 97/42206 PCTITSQ71fl77fl7 Micrococcus luteus ATCC 9341 0.05 0.05 0.05 Micrococcus luteus ATCC 4698 0.2 0.78 Escherichia coli JUHL >100 100 Escherichia coli SS 0.78 1.56 0.78 Escherichia coli DC-2 >100 >100 >100 Escherichia coli H560 50 50 Escherichia coli KNK 437 100 >100 100 Enterobacteraerogenes ATCC 13048 >100 >100 >100 Klebsiellapneumoniae ATCC 8045 >100 >100 Providenciastruartii CMX 640 >100 >100 >100 Pseudomonas aeruginosa BMH10 >100 >100 >100 Pseudomonas aeruginosa 5007 >100 >100 >100 Pseudomonas aeruginosa K799/WT 100 >100 >100 Pseudomonas aeruginosa K799/61 1.56 1.56 Pseudomonas capacia 2961 >100 >100 >100 Actinetobacter calcoaceticus CMX 669 12.5 25 12.5 Pseudomonas aeruginosa DPHD-5263 >100 >100 >100 Pseudomonas aeruginosa DPHD-2862 >100 >100 >100 Candida albicans CCH 442 >100 >100 >100 Mycobacterium smegmatis ATCC 114 3. 1 0.39 0.78 Nocarrdia asteroides ATCC 9970 0.1 It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and may be made without departing from the spirit and scope thereof.

-155-

Claims (2)

1- I z -z -I Z i- 156 The claims defining the invention are as follows: I. A compound having the formula R H,, Ra Rb 0,, (11); Y R F HO,. 6 C R a. 0 0 .set o* .00 000P .0 0.* (I0 S0 11 \DavibLIBXX]O2267.doc:aak WO 97/42206 WO 9742206PCT/US97/07702 0 a Rc IRd (IV); MV; (Vi); -157- (VII); too*

660.. 0604. 4 000 (VIII); and D H A N B" N (I X); as wvell as the pharm-aceuitically acceptable salts, formulae (11) (IX) above, X is selected from the group consisting of ester-s and prodrUgs thereof, wherein in 11 \DayLbI-IIRXN02267.doc ,.k WO 97/42206 PCTIUS97/07702 0 =0, =N-OH, =N-O-R 1 where R 1 is selected from the group consisting of unsubstituted C 1 -C12-alkyl, Cl-C 1 2-alkyl substituted with aryl, Cl-C 1 2-alkyl substituted with substituted aryl, Cl-C12-alkyl substituted with heteroaryl, Ci-C 12 -alkyl substituted with substituted heteroaryl, C 3 -C12-cycloalkyl, -Si-(R 2 )(R 3 )(R 4 wherein R 2 R 3 and R 4 are each independently selected from CI-C 1 2-alkyl, and -Si-(Aryl)3; and =N-0-C(R 5 )(R 6 )-0-R 1 where R 1 is as defined above and R 5 and R 6 are each independently selected from the group consisting of hydrogen, unsubstituted C 1 -C 1 2-alkyl, Cl-C 1 2-alkyl substituted with aryl, C 1 -C 12 -alkyl substituted with substituted aryl, C -C 12 -alkyl substituted with heteroaryl, and C -C 12 -alkyl substituted with substituted heteroaryl, or R 5 and R 6 taken together with the atom to which they are attached form a C 3 -C 1 2 -cycloalkyl ring; R a is hydrogen or hydroxy; Rb is hydrogen or hydroxy; one of Rc and Rd is hydrogen and the other of RC and Rd is selected from the group consisting of hydroxy, protected hydroxy, halogen, -159- PCTIVS97/07702 WO 97/42206 NR 7 R 8 where R 7 and R 8 are independently selected from the group consisting of hydrogen, CI-C 1 2-alkyl, substituted C I-C I2-allcyl, Cl-C 8 -cycloalkyl, substituted C I-C8-cycloalkyl, C I-C12-alkyl substituted with aryl, CI-C 1 2-alkyl. substituted with substituted aryl, C 1 -C 12 -alkyl substituted with heterocycloalkyl, CI-C 12 -alkyl substituted with substituted heterocycloalkyl, CI-C 1 2-alkyl substituted with Cl-C 8 -cycloalkyl, CI-C 12 -alkyl substituted with substituted C 1 -Cg-cycloalkyl, CI-C 1 2-alkyl substituted with heteroaryl, and (in) C 1 -C 1 2-alkyl substituted with substituted heteroaryl, (6) (7) (8) (9) and R 7 and R 8 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, 0-CO-NH-aryl, 0-CO-NH-heteroaryl, O-CO-NR 7 R 8 where R 7 and R 8 are as defined above, O-S0 2 -C 1 -C6-allcyl, O-S0 2 -(substituted C 1 I -C6-alkyl), 0-S0 2 -CH 2 -CH2-NR 7 R 8 where R 7 and R 8 are as defined above, or Rc and Rd taken together form the grouping selected from the group consisting of =0, =N-OH, and =N-0RI wherein RI is as defined above; 100 Re is methoxy, fluorine or hydroxy; Rf is hydrogen or a hydroxy protecting group; -160- PCTIUS97/07702 WO 97/42206 PTU9170 W is absent or selected from the group consisting of -NH-CO-, -N=CH- and -NH-; 105 R9 is selected from the group consisting of hydrogen, C I-C 6 -alkyl optionally substituted with one or more substituents selected from the group consisting of 110 aryl, substituted-aryl, heteroaryl, substituted-heteroaryl, hydroxy, 115 CI-C 6 -alkoxy, NR 9 R 10 where R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 -alkyl, or R 9 and R 10 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally 120 contain a hetero function selected from the group consisting of -N(substituted-aryl-C 1 -C6-alkyl-)-, -N(heteroaryl)-, -N(heteroaryl- C 1 -C6-alkyl-)-, -N(substituted-heteroaryl-CI-C6-alkyl-)-, and or wherein n is 1 or 2, 125 and -CH 2 -M-R I wherein M is selected from the group consisting of: (ii) 130 (iii) -NH-, (iv) -N(CH 3 (vi) -NH-C(0)-O- (vii) -NH-C(0)-NH- 135 (viii) -0-C(O)-NH- (ix) (xi) wherein n is 0, 1 or 2, (xii) 140 (xiii) -161- WO 97/42206 WO 9742206PCT[US97/07702 and (xiv) and RI I is selected from the group consisting of: Wi CI-C6-allcyl, optionally substituted with a substituent selected from the group consisting of (an) aryl, (bb) substituted-aryl, 145 (cc) (dd.) heteroaryl, and substituted-heteroaryl, 150 (iv) (v) aryl, substituted-aryl, heteroaryl, substituted-heteroaryl, 160 and (vi) heterocycloalkyl, C 3 -C 7 -cycloalkyl, aryl, substituted-aryl, heteroaryl, and substituted-heteroaryl; Rh is selected from the group consisting of hydrogen,_ hydroxy, -O-C(O)-imidazolyl, -O-C(O)-O-C 1 -C 6 -alkyl, -O-C(O)-O-aryl, -O-C(O)-O-(substituted aryl), and -O-C(O)-NH 2 R is selected (1) 175 from the group consisting of methyl substituted with a moiety selected from the group consisting of CN, F -162- PCT/US97107702 WO 97/42206 PTU9/70 -C0 2 RI 2 wherein R 12 is CI-C 3 -alkyl or aryl substituted CI-C3-allcyl, or heteroaryl substituted CI-C3-alkyl, 180 S(O)nRI 2 where n is 0, 1 or 2 and R 12 is as defined above, NHC(O)RI 2 where R 12 is as defined above, NHC(O)NR 13 RI 4 wherein R 13 and R 14 are independently selected from hydrogen and C I-C 3 -alkyl, aryl, 185 substituted aryl, heteroaryl, and substituted heteroaryl, C 2 -Clo-alkyl, 190 C 2 -Ci I -alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, Cl-C 3 -alkoxy, 195 CI-C 3 -alkoxy-C1-C3-alkoxy, oxo, -N3, -CHO, O-S0 2 -(substituted CI-C6-alkyl), 200 -NR I 5 R 16 wherein R 15 and R 16 are selected from the group consisting of hydrogen, (ii) C 1 -C 1 2-alkYl, (iii) substituted C I-C 12 -alkyl, 205 (iv) C 1 -C 12 -alkenyl, substituted C I-C 12 -alkenyl, (vi) CI-C 1 2-alkynyl, (vii) substituted C I-C 12 -alkynyl, (viii) aryl, 210 (ix) C 3 -C8-cYcloalkyl, substituted C 3 -C 8 -cycloalkyl, (xi) substituted aryl, (xii) heterocycloalkyl, (xiii) substituted heterocycloallcyl, -163- WA Q7142206 PCTIUS97/07702 0O9/20 215 (xiv) C 1 I -C I 2 -alkYl substituted with aryl, (xv) CI-C 12 -alkyl substituted with substituted aryl, (Xvi) CI-C 12 -alkyl substituted with heterocycloalkyl, (xvii) C 1 I -C12-all substituted with substituted heterocycloallcyl, (xviii) C 1 I-C 12-alkYl substituted with C 3 -C 8 -cycloalkyl, 220 (xix) C I-C I 2 -alkyl substituted with substituted C 3 -C8-cycloalkyl, (xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) CI-C 12 -alkyl substituted with heteroaryl, and 225 (xxiii) CI-C 1 2-alkyl substituted with substituted heteroaryl, or RI 5 and RI 6 are taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring which may be substituted with one or more substituents independently selected from the 230 group consisting of halogen, (ii) hydroxy, (iii) CI-C 3 -alkoxy, (iv) C 1 -C 3 -alkoxy-C 1 -C3-alkoxy, 235 oxo, (vi) CI-C3-alkyl, (vii) halo-C 1 -C3-alkyl, and (vii) C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl, 240 -C0 2 RI 2 wherein R 12 is as defined above, -C(O)NR I 3 R 14 wherein R 13 and R 14 are as defined above, =N-0-R 12 wherein R 13 is as previously defined, (in) -C=EN, O-S(O)nRI 2 wherein n is 0, 1 or 2 and R 12 is as defined above, 245 aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 8 -cycloalkyl, 250 substituted C 3 -C 8 -cycloalkyl, C I-C 12 -alkyl substituted with heteroaryl, -164- WO 97/42206 PCTIUS97/07702 255 260 265 270 275 280 285 (v (W (y) (aa) (bb) and heterocycloalkyl, substituted heterocycloalkyl, NHC(O)R 1 2 where R 12 is as previously defined, NHC(O)NR 13 RI 4 wherein R 13 and R 14 are as previously defined, =N-NR 15 R] 6 wherein R 15 and R 16 are as previously defined, =N-RI I wherein RI I is as previously defined, =N-NHC(O)RI 2 wherein R 12 is as previously defined, (cc) =N-NHC(O)NR I 3 R 14 wherein R 13 and R 14 are as previously defined; C 3 -alkenyl substituted with a moiety selected from the group consisting of halogen, -CHO, -C0 2 RI 2 where R 12 is as defined above, I where R I is as defined above, -C(O)NR 13 RI 4 wherein R 13 and R 14 are as previously defined, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C7-cycloalkyl, and CI-C 1 2-alkyl substituted with heteroaryl, C 4 -Cl 0 -alkenyl; C 4 -C 1 0 -alkenyl substituted with one or more substituents selected from the group consisting of halogen, C 1 -C3-alkoxy, oxo, -CHO, -C0 2 RI 2 where R 12 is as defined above, -C(O)NR 13 RI 4 wherein R 13 and R 14 are as previously defined, -NR 15 R 1 6 wherein R 15 and R 16 are as previously defined, =N-0-R 12 where R 12 is as previously defined, Wi -CN=N, O-S(O)nRI 2 where n is 0, 1 or 2 and R 12 is as previously defined, -165- WO 97/42206 PCT[US97/07702 0 aryl, 290 substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 7 -cycloalkyl, Ci-C 12 -alkyl substituted with heteroaryl, 295 NHC(O)R 12 where R 12 is as previously defined, NHC(O)NR 13 R 1 4 wherein R 13 and R 14 are as previously defined, =N-NR 15 R 16 wherein R 15 and R 16 are as previously defined, =N-R 11 wherein R 1 1 is as previously defined, =N-NHC(O)R 1 2 where R 12 is as previously defined, 300 and =N-NHC(O)NR 13 R 14 wherein R 13 and R 14 are as previously defined; C 3 -C 10 -alkynyl; and 305 C 3 -C10-alkynyl substituted with one or more substituents selected from the group consisting of trialkylsilyl, aryl, substituted aryl, 310 heteroaryl, and substituted heteroaryl; one of Y and Z is hydrogen and the other is selected from a group consisting of 315 hydrogen, hydroxy, protected hydroxy, and NR 7 R 8 wherein R 7 and R 8 are as defined above; 320 and A, B, D and E, with the provision that at least two of A, B, D and E are hydrogen, are independently selected from the group consisting of: 325 hydrogen; -166- WO 97/42206 PCT/US97/07702 C I-C6-alkYl, optionally substituted with one or more substituents, selected from the group consisting of: Wi aryl; (ii) substituted-aryl; 330 (iii) heteroaryl; (iv) substituted-heteroaryl; heterocycloalkyl; (vi) hydroxy; (vii) CI-C 6 -alkoxy; 335 (viii) halogen consisting of Br, Cl, F or 1; and (ix) NR 9 R 1 0 wherein R 9 and RIO are as defined above; C 3 -C 7 -cycloalkyl; aryl; substituted-aryl; 340 heteroaryl; substituted-heteroaryl; heterocycloalkyl; and a group selected from option above further substituted with -M-R 11 I wherein M and R 1 I are as defined above; 345 or any one pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7- membered ring optionally containing a hetero function selected from the group consisting of-O-, -N(C 1 -C6-alkyl-)-, -N(aryl-C I -C6-alkyl-)-, 350 -N(substituted-aryl-C I -C 6 -alkyl-)-, -N(heteroaryl-C I -C 6 -alkyl-)-, -N(substituted-heteroaryl-CI-C6-alkyl-)-, or wherein n is 1 or 2, -C(O)-NR 12 wherein R 1 2 is as defined above, -NR 12 wherein R 12 is as defined above, and 355 -167- PCT/US97/07702 WO 97/42206 2. A compound according to Claim 1 having the formula wherein X, R, R a Rb, Rc, Rd, R e and R f are as defined therein. 3. A compound according to Claim 2 wherein R a is hydroxy, Rb is hydrogen, R c is hydrogen, Rd is hydroxy, Re is methoxy, and R f is hydrogen. 4. A compound according to Claim 1 having the formula Y R R' NMe 2 z I 01". 6 Ra "0 o Rb OR 0 RRc R e R wherein Y, Z, R, R a Rb, Rc, Rd, Re and R f are as defined therein. A compound according to Claim 3 wherein R a is hydroxy, Rb is hydrogen, Re is hydrogen, Rd is hydroxy, Re is methoxy, and R f is hydrogen. -168- 0 WO 97/42206 6. PCTIUS97/07702 A compound according to Claim 1 having the formula Re N wherein R, R b Rc, Rd, Re and R f are as defined therein. 7. A compound according to Claim 1 having the formula wherein R, Rb, Rc, Rd, Re and R f are as defined therein. -169- WO 97/42206 8. PCT/US97/07702 A compound according to Claim 1 having the formula Re wherein R, Rb, Rc, Rd, R e R f and Rh, are as defined therein. 9. A compound according to Claim 1 having the formula wherein W, R, Rb, Rc, Rd, R e R f and Rg are as defined therein. -170- 0 WO 97/42206 10. PCT/US97/07702 A compound according to Claim 1 having the formula wherein A, B, D, E, R, Rb, Rc, Rd, Re and R f are as defined therein. 1 11. A compound according to Claim 1 having the formula 2 EL, R R' NMe 2 A I Rb O O 6O RR O "R d c 3 Re 4 wherein A, B, D, E, R, Rb, Rc, R d Re and R f are as defined therein. 6 12. A compound according to Claim 1 which is selected from the group consisting of: compounds wherein A, B, D, E, W, X, Y, Z, R, R a Rb, R c Rd, R e R f Rg and Rh are as previously defined, and R is selected from the group consisting of: (1) (2) (3) -171- WO 97/42206 PCTIUJS97/07702 NO2 CN 1 2) 0 H 3 3) O N.' N- (11) OH 3 -172- O WO 97/42206 (17) (18) N (19) 'N N (21) (22) 0 (23) (24) N0 2 -Y OCH 3 0.-H 3 (26) -mr- NH 2 (27) (28) CH 3 (29) c PCTIUS97/07702 -173- 174 S 0 0 (31) ;and H B r (32) compounds of formula (11) wherein W' is is HI R' is s1-1:R d is OH; R' is me~IhONNI: R" i 1-1, whereinRis selected From11 the groupJ Con1sisting 0f OH OH 0 H CH 3 04 H (4) CH 3 *00400~(5) N OH 3 ~0 (6)N NH 2 0 0 so0 N' NH 2 0 t o N0H H OH 3 (11) O- CH 3 II 1A) Ib\L113X X 102 27. docak WO 97/42206 PCTIS97/07702 CH 3 (12) OH 3 OH 3 (13) CH3 (14) O l SeS CH3. (16) O 0, CH3 (17) (18) (19) H 3 SCHO (21) OH 3 (22) N0 2 (23) (24) 9 00H 3 CN (26) (27) -175- WO 97/42206 0 (28)OH (29) C H 3 ~O 3 (31) *"o (32) OH 3 (33) (34) O 3 N (36)N N (39) O 2 OC0H 3 (41)0 PCT[US97/07702 -176- 177 -11 yNH 2 (42)0 0 (43) OH 3 0 (44) S (46)0 0ad H (47) r aI compound of Formula therein wherein X is Rh is 1-1; R' is H; Rd Is acetyl Re is methoxy; R" is acetyl; R is -CI-L-CH=C[l-l a compound of Fornmula thereini which is selected f'romn the group wherein R" is H; Re is H; R d is phenylmethyloxycar-bonyl; R' is mnethoxy; R" is HI; R is -CH 2 -CH=CH 2 and b d A ReiRis-'Rs R is H; Rc is H; R is hyd 1 roxy; Rci methoxy;R"iH;R s A -CH 2 -CH=CH 2 (Ii a compound of Formula (VI) therein which is selected f-rm the group wherein R" is H; R' is H; is phenyli-dithyloxycarbonyl; R' is i-ethoxy; is acetyl; R is -CH 2 -CHI=CI-1 2 and (I \[)ayLib\LIBXX]02267 docaak 178 a compound of Formula (ViI) therein which is selected fromn thle group wherein W is -N11-; Rb) is H; R' is 11; R d IS phenylmethyloxycarbonyl; R' is methoxy; R" is H; R, is 1-1; R is propyl; W is R" is H; Rc is 1-I; R d is phienylmethyloxycarbonyl; R' is ~methoxy; R" is H; R' is H; R is -CH 2 -CH=CH 2 W is absent; R b is 1-1; R' is Rd is phienylmethiyloxycarbonyl;, R' is mnethoxy; is acetyl; is 4-phenylbuityl; R. is -CH 2 -CH=C- 2 W is absent; R" is R' is II; R d is p)henylmethyloxycarbonyl; R' is methoxy; R" is W- is 4-p)henylbutyl; R is -CI-B?-Cl-1-=CU 2 WA is absent;, Rh is Rc is H,1 Rd is phienylmiethiyloxycar-boniyl;, R is methoxy; R' is acetyl; R is 4-phenylbutyl; R is -Cl-B-Cl 1=CH 2 quirnoliny 1); W is absent; R b is H; R' is is phienylmiethyloxycarbonyl; R' is methoxy; R" is H; R is 4-phenylbutyl; R is -Cl-)-C1-=Cl-?-(3)-quinolinyl); b (I d W is absent; R" is Rc is H; R. is acetyl; R' is methoxy; R" is acetyl; R" is H; R is -CH 2 -CH=CH- 2 W is absent; Rb is H; Rc is H; R( is acetyl; R' is methoxy; R" is acetyl; R" :is H; R is -CH 2 -CI-ICH 2 )-quinolinyl); W is absent; R is H; R' is H; Rd is acetyl; R' is methoxy; R" is H; R" is H; R is -CH 2 -CH=CH 2 -('3-quinoliny1); W is absent; R b is H; Rc is H; Rd is methoxy;, R' is methoxy; R" is H; R, is 1-I; R is -C1J-ICH=CH?1-(3-quinolirnyl); (11) W is absent; R is IH; R' is L1; R' is methoxy; Rd' is ethensulfonyloxy; R" is acetyl; is H; R is -CHCI-=C11-(3-quinolinyl); (122) W is absent; is R' is H; R' is mrethoxy; R~ is 2 (dimethylarnino)ethiylsulfonyloxy; R" is acetyl; R, is 11I; R is -CHCH=CH 2 -quinolinyl); (1 3) W is absent; R i1s RC i s 1-I; Rd Is methoxy; R' is 2-(phenylthio)ethoxy; is acetyl; Rg is I-1, R Is -CH2C 7 CH--(3)-quiniollinyl), 11 \D~iyi,il\LIB1XNO2267.(Ioc.aik 179 (14) W is absent; Rt is H; R' is H; R d is methoxy; R' is (2- niitrophienyl)aminocarboinyloxy; R" is H4; R, is H; R. is -CI- 2 CH=CH 2 -(3 quinolinyl); and W is absent; R" is 1-I; R' is H; is methoxy; R' is (2 -nitro phenyl)aminoc arbony loxy; R" is R, is H, R is -CH 2 CH=CH 2 quinol inyl); a compound of formula (11) wherein W. is 01H; Rtis PR' is 1-1, RtI is O1-; Rc Is mctIoNN:_ R' is H.1 selected from the group consisting Of compouinds wherein X is R is -CIll-CI-=CH- 2 -(3)-quinoliinyl); I u(2) X is R is allyl; )X is =N-OH, R is allyl; X is R is propyl; X is R is 2,3-dihydroxypropyl; X is R is 2,3-epoxypropyl; X is P. is 2-hiyd-ox\v-3-(iimiidazol-1-yI)propyl, X is R is 2-hiydroxy-3)-(m--orpholiin-4-yl)propyl; X is R is 2-hydroxy -3 enzylIarnino) propy]; X is R is 2-oxoethyl; (11) X is R is 2-oxopropyl; (12) X is =N-0-(l-isopropoxycyclolhexyl), P. is -CH- 9 -CJCH; P. is -CH- 9 -CJCH, X is =N-0-H; (14) X is P. is -Ci-i 2 -CJC i-; (15) X is R is -CI- 2 -CHOH-CI-1-N 3 (16) X is R is -CH 2 -CI-I=N-OH; (17) X is R. is -CH 2 -CH-0H; (18) X is R is -CH 2 -CH- 2 NH-); (19) X is Ris -CH 2 -CN:. X is P. is -CI-1-phenyl; (21) X is R is -CH-)-CH=CH-phenyl-; AU(22) X is R is -CH 2 -CH=N-0-CI1 3 (23 X is R is -CH 2 -CI-=N-0-CI- 2 -PhenYl; (24) X is R is -CI- 2 -CH=N-N(C- 3 2 X is R is -CH 2 -CI-=N-NI-1(CH 3 (26) X is R is -CH 2 -CH=N-(4-rnorpholinyl); (27) X is P. is -CH- 9 -CH=N-NH(phenyl); and I I\DayIh\IIBXXIO2267.dOC ank 180 (28) X is R is -CI- 2 -CH=N-N(phenyl) 2 (29) X=0, R~phenylpropy1; X=0, R IS -CH1 2 CI-=CH-(4-methylph-enyl); (31) X=0, R is CH 2 -CH(OH)-phenyl; (32) X0O, R is -CH 2 -CH(Br)-CJ-bBr; (33 X=0, R is -CHCI L 9 NI-CH)C1-1)C[1-pheniyl- (34) X=0, R is -CI)C-NIIC-(CL)l 2 PeniyI)CO 2 Me; X=0, R is -CJ- 2 CH 2 NHCH)CI-b-CH- 3 (36) X=0, R is -CH-)CI-bNL-CHCOCW1CL I?- I U(37) X=0, R is -CL-LCH 9 NHCH- 2 CI--phenyL: (38) X=0, R is -CLL-CI-LNHCI-1 2 C1--(4-hydr-oxyipleny):- (39) X=0, R is -ClI1 2 CH- 2 NHCH 2 CI-1-(-h-ydiroxyphienyl); X=0, R is -CI- 2 C1-LN IICI-1)CH-(-metlhoxyphleinyl): (41) X=0. R is -CI-LCI-LNI-ICH- 2 CH- 2 9 -iethioxyph~lcnyl): X0O, R is -CH 2 CH 2 NHCH 2 CI-1-(4-metihoxyplicny l): (43 X=0, R is -CH 2 CH 2 NHCH 2 )-phenyl; (44) X is =N-0-(1-isopropoxycyclohexyl), R is BlUoromethyl; X=0, R is -CH 2 CI- 2 NHCH 2 CH 2 -(3-chlor-opheniyl); X=0, R is -CI-I 2 CH 2 NHCH 2 CH-(2-chiloropheinyl); 3(47) X=0. R is -CH 2 CH 2 NHCH 2 CH 2 -(4-chloroplheiyl);. (48) X=0, R is -C1H2CH NI-CI- 2 CH1---ny1;'), (49) X=0, R is -CH2CH 2 NHCH 2 C- 2 C1-1-(-quliiolinyl); (50) X=0, R is -CH 2 CH 2 NHCI- 2 CH 2 CHI 2 -qunliyl; (51) X=0, R is -CH 2 -)CH=N-C 2 CH- 2 Crii-y1 2 -ey 23(52) X0O, R is -CI-1? 2 -CH-=N-NI-p-CO)NH 2 X=0, R is -C--CI-1=N-NHC-pyidinyl)iii X=0, R is -CI-L-CH=(4-met12HClipc)-4:raicl); (58) X is R is (3)-iodophenyl)rnethyl; and (59) X is R is (4-fluorophenyl)irnethyl; I .[ulIAAL~ IbXX 102207 Iocnak 181 a compound of formula (II) wherein is 01-I; is H; Rc is 11~ R) is OH; Re is nctboxy: V is H; X is 0: R is CH 2 CH(OH)~CI~l 2 RV; and RV is selected iTom the ~.roup consishflc ol: N (i)Y a a. .aa a a a. a a a a. a a. a a a a a a a a a. a a a a a a a a 11 \I)ii~i-ib\Il3lXX1O2267dtocA ak PCT/US97/07702 WO 97/42206 N 245 (3) (4) OH (6) (7) 250 (8) (9) <"s N" (11) (12) 255 (13) (14) (16) (17) 260 (18) (19) -182- SUBSTITUT SHET (RULE 26) PCTJIJS97/07702 WO 97/42206 0 (21) ome (22) 265 (23) ~k (24) .3IT (26) CF 3 (27) N 270 (28) (29) (30)0 OH (31)CI (32) OH 275 (33) (34) OH (36) -183- SUBSTITUTE SHEET (RULE 26) WO 97/42206 PCTIUS97/07702 OMe SOMe (37) 280 (38) (39) \NYQ (41) ITO clC (42) 285 (43) (44) \N4) CN; OMe (46) L (46) OMe OMe 290 (48) OMe (49) (51) -184- SUBS =if If (UE 26) WO 97/42206 PCT/US97/07702 (52) N F 295 (53) (54) c N0 2; (56) (57) r" OH 300 (58) (59) (61) OH (62) 305 (63) (64) OMe (66) (67) -185- SUBSn E SHEE (RULE 26) WO 97/42206 PCT/US97/07702 0 310 (68) NO (69) (71) XNC 1 (72) oxk (73) CI; 315 (74) (76) (77) uN OMe ^-N 320 (78) (79) and ~NQOr, 325 a compound wherein X is O, R is CH 2 -CH2-RW,and R W is selected from the group consisting of: PI N OMe. -186- SuBSm SHEET (RULE 26) WO 97/42206 PCTIUS97/07702 (4) 330 (6) (7) (,-,WOF3 (9) \N J 2 335 (11) (12) F (13) K cl (14) \N3 OMe 340 (16) OMe IC (18) \N -187- S muE~ SHEET (RULE 26) WO 97/42206 PCTIUS97/07702 (19) r~QCF3 345 (21) ome (22) (23) (24) r NO2 350 (26) LO >rCF 3 (27) <rQO (28) \NQ SMe (29) 0 355 (31) OMe ~Me (32) -188- SU&SM SHET (RULE 26) WO 97/42206 PCTIUS97/07702 ~qrF (33) F (34) 360 (36) N*1 (37) (38) \14- cl (39) N- OMe 365 (41) (42) (43) CI (44) 370 (46) -189- SUBSTITUTE SHEET (RULE 26) wn 7/dn06 PCT/US97/07702 WO 972206 OMe r j OMe Nr^ OMe (47) and (48) a compound wherein X is O, R is CH 2 -CH=N-RX, and RX is selected from 375 the group consisting of: (1) N (3) H \N CN; 380 N N (6) X Z. H OZ NO2 385 (10) o ;and (11) o and a compound wherein R a is OH; Rb is H; RC is H; Rd is RP; Re is methoxy; 390 Rf is RP; selected from the group consisting of compounds wherein: X is =N-O-(1-isopropoxycyclohexyl), R is allyl, RP is Trimethylsilyl X is =N-O-(1-isopropoxycyclohexyl), R is -CH2-Phenyl, RP is Trimethylsilyl; X is =N-O-(1-isopropoxycyclohexyl), R is -CH2-Phenyl, RP is H; 395 and -190- SUBSTITUTE SHEET (RULE 26) 191 X is =N-OH, R is -CH 2 -Phenyl, R" is H;, and pharmaceutically acceptable salts, esters and prodrugs thereof. 13'. A compound of formula (11) according to claim 3) which is selected from the (£'YouLp Consisting Ot a compound wherein W' is 01-1, R" is Is11 RC Is 1-I; RdI is 01; R' is mnethoxy; R" is 1I: selected Cromi the grouIp Consisting of comp-ounds \vhiercin X is R is -CH-b-Cl-l=CI-(3)-quitnoliinyl): X is R is allyl; X is =N-011, R is allyl; H(4) X Is R is propyl;, X is R is '-.3'-dihy)droxypr)iopl:1 X Is R is 2.3-epoxy propyl X is R is 2-lwdi-oxy-3)-(Iimidazol-l-ylI)prolpyl, X Is R is 2-hvNdroxy,-3-(miorphlollin-4-ylil)rop~yl; 5(9) X is R is 2-1hydroxy-3)-(benizylainio)propyl;, X is R is 2-oxoethyl; X is R is 2-oxopropyl; (12) X is =N -0-(l1-isopropoxycyclohexyl), R is -C I--CJCH; Ris -CI-1 2 -CJCH, X is =N-0-H; in(14) X is R is -CHI-cCHI; X is R is -CH- 2 -CHOH-C1 2 -N_ 3 (16) X is R is -CH 2 -CH=N-01-; (17) X is R is -CH 2 -CH 2 OH4; (1 8) X is R is -CH 2 -CI- 2 NH-) )3 (19) X is R is -CH-)-CN- X is R is -CI-1-phenyl; (21I) X is R is -Cl-h-CH =CI-l-pl-enyl-;' (22) X is R is (23 X is R is -CH?-C1l1=N-0-CI- 2 -phenyl; 10(24) X'is R is -CH- 2 -CI-=N-N(C-1 3 2 X is R is -CI1 2 -CH=N-NH(CH 3 (26) X is R is -CH 2 -CH=N-(4-rnorpholinyl); (27) X is R is -CH-)-C1-kN-N1I(p-heny1); and (28) X is R IS -CI-1 2 -CI-1N-N(phenyl) 2 (29) X=0, R=PhenylIprop),l; I .\IayLibULBXXj02267 doc:aak WO 97/42206 WO 9742206PCTIVS97/07702 0 X=0, R is -CH2CH=CH-(4-rnethylphenyl); (31) X=0, R is -CH2-CH(OH)-Phenyl; (32) X=O, R is -CH2-CH(Br)-CH2Br; (33) X=O, R is -CH2CH2NHCH2CH2CH2-Phenyl; (34) X=O, R is -CH2CH 2 N1HCH(CH2Phenyl)CO2Me; X0O, R is -CH 2 CH 2 NHCH2CH2CH3; (36) X=0, R is -CH 2 CH 2 NHCH2CO2CH2CH2; (37) X=O, R is -CH 2 CH 2 NI1CH2CH2-Pheny1; (38) X=O, R is -CH 2 CH 2 NHiCH2CH2-(4-hydroxypheny1); (39) X=O, R is -CH 2 CH 2 NHiCH2CH2-(3-hydroxypheny1); X=O, R is -CH 2 CH2N]HCH2CH2-(3-methoxyphenyl); (41) X=O, R is -CH 2 CH 2 NHiCH2CH2-(2-methoxyphenyl); (42) X=O, R is -CH 2 CH 2 N-HCH2CH2-(4-methoxypheny1); (43) X=O, R is -CH2CH2NHCH2-phenyl; (44) X is 1 -isopropoxycyclohexyl), R is fluoromethyl; X=O, R is -CH2CH2NI1CH2CH2-(3-chlorophenyl); (46) R is -CH 2 CH2NHCH2CH2-(2-chlorophenyl); (47) X=O, R is -CH 2 CH2N}1CH2CH2-(4-chloropheny1); (48) X=O, R is -CH2CH2N1CH2CH2-O-phenyl); (49) X=O, R is -CH 2 CH2NHCH2CH2CH2-(4-quinolinyl); X0O, R is -CH2CH2NHCH 2CH2CH2-(3-quinoliny1); (51) X=O, R is -CH 2 CH2NHCH2CH2CH2CH2-pheny1; (52) X=O, R is -CH2-CH=N-NH-C(O)-NH2; (53) X=O, R is -CH2-CH=N-NH-(2-pyridinyl); (54) X=O, R is -CH 2 -CH=N-(4-methylpiperazinyl); X=O, R is -CH2-CH=N-O-phenyl; (56) X=O, R is -CH 2 CH(OH)CH2NHCH2CH2-phenyl;, (57) X=O, R is -CH 2 CH(OH)CH2NHCH2-(4-pyridiny1; (58) X is R is (3-iodophenyl)methyl; and (59) X is R is (4-fluorophenyl)methyl; a compound wherein Ra is OH; Rb is H; RC is H; Rd is H; Re is methoxy; Rf is H; X is 0; R is CH 2 -CH(OH)-CH2-RV and RV is selected from the group consisting of: (1)ni -192- SIJSf1T SNEE (RmUL26 WO 97/42206 PCT1US97107702 (3) (4) OH (6) (7) (8) (9) (12) (13)0 (14) (16) (17) (18) (19) x o SUBSTITUTE -S 1 HEET (RULE 26) WO 97/42206 (21) O OMe I OMe (22) (23) (24) (26) .F; (27) CF (28) (29) N OH (31) xC (32) -OH. OH (33) 100 (34) OH (36) OMe <SOMe (37) N (38) -194- SUBSTITUTE SHEET (RULE 26) PCT/US97/07702 WO 97/42206 PCTIUS97/07702 105 (39) N02N0 \O 2 V (41) N'C I (42) (43) 110 (44) CN. OMe K-NiIMe (46) OMeQ (47) 1Ns ome 115 (49) CI (51) (52) F (53) -195- SUBSTITUTE SHEET (RULE 26) WO 97/42206 0 120 (54) (56) (57) (58) XOH 125 (59) N (61) (62) (63) 130 (64) OMe (66) (67) (68) 135 (69) -196- SUB=sII SHELT (RULE 26) PCT/US97/07702 WO 97/42206 PCT/US97/07702 (71) X (72) "N (73) C; 140 (74) N I (76) OMe rKN (77) F (78) F; and 145 (79) a compound wherein X is O, R is CH 2 -CH2-RW, and R W is selected from the group consisting of: (1) (2) 150 N.L OMe; 0 -197- SUBSm T sEE (RuLE 2) WO 97/42206 PCT[US97/07702 <rQ (7) rlW CF3 155 c 9N.) N,) (12) xN- 160 (13) C <l (14) (16) (17) \kN) N. CI 165 (18) (19) -198- SU M HE(IU 6 PCT[US97/07702 WO 97/42206 CF 3 (21) OMe (22) 170 (23) (24) NO 2 (26) cI K CF 3 (27) 175 (28) SMe. (29) cl~c (31) OMe (32) 0 180 (33) -199- SUBSTITUTE SHEET (RULE 26) PCTIUS97/07702 WO 97/42206 (34) F <N (37) 185 (38) N Q CI (39) N" (41) (42) \4,j C,) (44) u. (46) OMe (47) and -200- SUBTITTESHE~i (R L 26 28/07/00 N ;and is 0, R is CH 2 -CH=N-Rx, and Rx is selected from (48) a compound wherein X the proup consisting of: S S *S S S S. S S *S S N VN H ON N3 N N N H N 7 0 2 Na NO 2 Ny 0 (9) 11 \[)ayLib\[,IIXX]O22('7 doc ank 28/07/00 201 o. H (11) 0 is well as the pharm-aceutically acceptable salts, esters and prodrugs thereof. 14. A comnpound of formula (11) according to claim 1'3 wherein is OH; R" is H, pk' is R' is 01-1; R' is mnethoxy; Rf is H; selected from the group consisting of compounds S wherein: X is R is -CH 2 -CH=CH 2 -('3-quinolinyl); X is R is allyl; X is R is 2-hiydr-oxy-3)-(benizylainio)propl1: X is R is 2-oxopropyl; X is R is X is R is -CH- 2 CI-=N-OH; X is R is -CH 2 -CH 2 -OH; X is R is -CH- 2 -CH 2 NI1 2 and X is R is -CI-b-CN. 11 \DayLI\IA1ABXO?2267.doc aa A 6-O-substituted erythromycin derivative, substantially as hereinbefore described with reference to any one of the Examples. 16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 15 in combination with a pharmaceutically acceptable carrier. 17. A method for controlling a bacterial infection in a mammal comprising administering to an animal a therapeutically effective amount of a compound according to any one of claims 1 to 15 or of a composition according to claim 16. 18. A compound according to any one of claims 1 to 15 or a composition according o to claim 16 when used to control a bacterial infection. 19. Use of a compound according to any one of claims 1 to 15 in the manufacture of S• a medicament for controlling a bacterial infection. •20. The method, compound or use according to any one of claims 17 to 19 wherein the compound is a compound of claim 12. is 21. The method, compound or use according to any one of claims 17 to 19 wherein the compound is a compound of claim 13. o: 22. The method, compound or use according to any one of claims 17 to 19 wherein the compound is a compound of claim 14. 0 0o 4 °a 0 00000 0 [/libxx]01070:MEF WO 97/42206 PCTIUS97/07702 23. A process for the preparation of 6-0-substituted macrolide compounds having the Formulae: xR Rf NMe 2 H Ra6 R b 0 0 R e~Ne 01", R e0 0 R b 0 ,0. 0 RR 0 Id) R Rf NMe 2 04 6 01 Rb 0, 0 Re (IV); -203- WO 97/42206 PCT/US97/07702 (VI); wg (VIED; -204- WO 97/42206 WO 9742206PCT1US97/07702 (yin); and (IX); wherein X is selected from the group consisting of =0, =N-OH, =N-0-RI where RI is selected from the group consisting of unsubstituted C I-C 1 2-alkyl, C I-C 12 -alkyl substituted with aryl, C I-C 12 -alkyl substituted with substituted aryl, C I-C 12 -alkyl substituted with heteroaryl, C I-C I 2 -alkyl substituted with substituted heteroaryl, C 3 -C 1 2 -cycloalkyl, -Si-(R 2 )(R 3 )(R 4 wherein R 2 R 3 and R 4 are each independently selected from CI-C 12 -allcYl, and -205- WO 97/42206 PCT/US97/07702 -Si-(Aryl)3; =N-O-C(R 5 )(R 6 )-O-R 1 where R 1 is as defined above and R 5 and R 6 are each independently selected from the group consisting of hydrogen, unsubstituted Ci-C 12 -alkyl, C 1 -C 1 2-alkyl substituted with aryl, C 1 -C 12 -alkyl substituted with substituted aryl, C1-C 12 -alkyl substituted with heteroaryl, and C 1 -C 1 2-alkyl substituted with substituted heteroaryl, or R 5 and R 6 taken together with the atom to which they are attached form a C 3 -C 12 -cycloalkyl ring; R a is hydrogen or hydroxy; Rb is hydrogen or hydroxy; one of Rc and Rd is hydrogen and the other of R c and Rd is selected from the group consisting of hydroxy, protected hydroxy, halogen, NR 7 R 8 where R 7 and R 8 are independently selected from the group consisting of hydrogen, Cl-C 12 -alkyl, substituted C -C 12 -alkyl, C 1 -Cg-cycloalkyl, substituted C 1 -Cg-cycloalkyl, C -C 1 2 -alkyl substituted with aryl, C 1 -C 1 2-alkyl substituted with substituted aryl, C 1 -C 1 2-alkyl substituted with heterocycloalkyl, C 1 -C12-alkyl substituted with substituted heterocycloalkyl, C 1 -C 12 -alkyl substituted with C -Cg-cycloalkyl, C 1 -C 1 2 -alkyl substituted with substituted C 1 -Cg-cycloalkyl, -206- PCT/US97/07702 WO 97/42206 C 1 -C 12 -alkyl substituted with heteroaryl, and C 1 -C 12 -alkyl substituted with substituted heteroaryl, or R 7 and R 8 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, O-CO-NH-aryl, O-CO-NH-heteroaryl, O-CO-NR 7 R 8 where R 7 and R 8 are as defined above, O-S0 2 -Cl-C6-alkyl, O-S0 2 -(substituted C 1 -C 6 -alkyl), and O-S0 2 -CH 2 -CH 2 -NR 7 R 8 where R 7 and R 8 are as defined above, or Rc and Rd taken together form the grouping selected from the group consisting of =0, =N-OH, and =N-OR 1 wherein R 1 is as defined above; 100 Re is methoxy, fluorine or hydroxy; R f is hydrogen or a hydroxy protecting group; W is absent or selected from the group consisting of -NH-CO-, -N=CH- and -NH-; 105 Rg is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl optionally substituted with one or more substituents selected from the group consisting of 110 aryl, substituted-aryl, heteroaryl, substituted-heteroaryl, hydroxy, 115 C 1 -C 6 -alkoxy, -207- WO 97/42206 PCTIUS97/07702 NR 9 RI 0 where R 9 and RIO are independently selected from hydrogen and CI-C 6 -alkyl, or R 9 and RIO are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally 120 contain a hetero function selected from the group consisting of -N(C 1 -C6-alkyl-)-, -N(aryl)-, -N(aryl-Ci -C6-alkyl-)-, -N(substituted-aryl-Ci -C6-alkyl-)-, -N(heteroaryl)-, -N(heteroaryl- CI-C6-alkyl-)-, -N(substituted-heteroaryl-CI-C6-alkyl-)-, and or wherein n is 1 or 2, 125 and -CH 2 -M-R I wherein M is selected from the group consisting of: (ii) 130 (iii) -NH-, (iv) -N(CH 3 (vi) -NH-C(O)-O- (vii) -NH-C(0)-NH- 135 (viii) -O-C(0)-NH- (ix) (xi) wherein n is 0, 1 or 2, (xii) 140 (xiii) and (xiv) and RI I is selected from the group consisting of: 145 Wi CI-C6-alkyl, optionally substituted with a substituent selected from the group consisting of (aa) aryl, (bb) substituted-aryl, (cc) heteroaryl, and 150 (dd) substituted-heteroaryl, (ii) aryl, (iii) substituted-aryl, -208- WO 97/42206 PCTIUS97/07702 (iv) heteroaryl, substituted-heteroaryl, 155 (3) (4) (6) and (7) and (vi) C 3 -C 7 -cycloalkyl, aryl, substituted-aryl, heteroaryl, heterocycloalkyl, 160 substituted-heteroaryl; 165 170 175 Rh is selected (1) (2) (3) (4) (6) (7) (8) R is selected (1) from the group consisting of hydrogen, hydroxy, -O-C(O)-im-idazolyl, -O-C(O)-O-C 1 -C 6 -alkyl, -O-C(O)-O-aryl, -O-C(O)-O-(substituted aryl), and -O-C(O)-NH2; from the group consisting of methyl substituted with a moiety selected from the group consisting of CN, F, -C0 2 RI 2 wherein R 12 is CI-C 3 -alkyl or aryl substituted C 1 -C 3 -alkyl. or heteroaryl substituted C 1 I -C 3 -alkyl, S(O)nRI 2 where n is 0, 1 or 2 and R 12 is as defined above, NHC(O)R 12 where R 12 is as defined above, NHC(O)NR 13 RI 4 wherein R 13 and R 14 are independently selected from hydrogen and C 1 -C 3 -alkyl, aryl, substituted aryl, heteroaryl,_ (g) (h) and substituted heteroaryl, C 2 -CIO-alkYl, -209- WO 97/42206 PCTIUS97/07702 190 (3) group 200 205 C 2 -C I 0 -alkYl substituted with one or more substituents selected from the consisting of halogen, hydroxy, Cl-C 3 -alkoxy, CI-C 3 ~alkoxy-C1-C3-alkoxy, oxo, -N 3 -CHO, O-S0 2 -(substituted Ci-C6-alkyl), -NR I 5 R 16 wherein R 15 and R 16 are selected from the group consisting of hydrogen, (ii) CI-C 12 -alkyl, (iii) substituted C I-C I 2 -alkyl, (iv) Cl-Ci 2 -alkenyl, substituted C I-C 12 -alkenyl, (vi) CI-Ci 2 -alkynyl, (vii) substituted CI -Ci 2 -alkynyl, (viii) aryl, (ix) C 3 -C 8 -cycloalkyl, substituted C 3 -C8-cycloalkyl, (xi) substituted aryl, (xii) heterocycloalkyl, (xiii) substituted heterocycloalkyl, (Xiv) C 1 -C 12 -alkyl substituted with aryl, (xv) CI-C 12 -alkyl substituted with substituted aryl, (xvi) CI-C 1 2-alcyl substituted with heterocycloalkyl, (xvii) CI-C 12 -alkyl substituted with substituted heterocycloalkyl, (xviii) Cl-C 12 -alkyl substituted with C 3 -C 8 -cycloalkyl, (xix) CI-C 12 -alkyl substituted with substituted C 3 -C 8 -cYcloalkyl, (xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) CI-C 12 -alkyl substituted with heteroaryl, and (xxiii) C I-C 12 -alkyl substituted with substituted heteroaryl, 210 215 220 225 -2 .0 WO 97/42: 230 235 240 245 250 255 260 0O6 PCTIUS97/07702 R 15 and R 16 are taken together with the atom to which they are attached form a 3- 10 membered heterocycloallyl ring which may be substituted with one or more substituents independently selected from the group consisting of halogen, (ii) hydroxy, (iii) CI-C3-alkoxy, (iv) C 1 -C 3 -alkoxy-Cl-C3-alkoxy, oxo, (vi) C 1 -C 3 -alkyl, (vii) halo-Cl-C3-alkyl, and (vii) Ci I-C 3 -alkoxy-C I -C 3 -alkyl, -C0 2 RI 2 wherein R 12 is as defined above, -C(O)NR 13 RI 4 wherein R 13 and R 14 are as defined above, =N-0-R 12 wherein R 13 is as previously defined, (in) O-S(O),R 1 2 wherein n is 0, 1 or 2 and R 12 is as defined above, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 8 -cycloalkyl, (t0 substituted C 3 -C 8 -cycloalkyl, Mu CI-C 1 2-alkyl substituted with heteroaryl, heterocycloalcyl, substituted heterocycloalkyl, NHC(O)Rl 2 where R 12 is as previously defined, N HC(O)NR 13 RI 4 wherein R 13 and R 14 are as previously defined, =N-NR 15 R 16 wherein R 15 and R 16 are as previously defined, (aa) -N-RI I wherein RI I is as previously defined, (bb) =N-NHC(O)RI 2 wherein R 12 is as previously defined, and (cc) =N-NHC(O)NR I 3 R'1 4 wherein R 13 and R 14 are as previously defined; C 3 -alkenyl substituted with a moiety selected from the group consisting of halogen, -211- WO 97/42206 PCTfUS97/07702 -CHO, 265 -C0 2 RI 2 where R 12 is as defined above, -C(O)-Rl I where RI I is as defined above, -C(O)NR 13 RI 4 wherein R 13 and R 14 are as previously defined, aryl, 270 substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 7 -cYcloalkYl, and 275 Cl-C 12 -alkyl substituted with heteroaryl, C 4 -CIO-alkenYl; C 4 -C I 0 -alkenyl substituted with one or more substituents selected from the group consisting of halogen, 280 C 1 -C 3 -alkoxy, oxo, -CHO, -C0 2 RI 2 where R 12 is as defined above, -C(O)NR 13 R 14 wherein R 13 and R 14 are as previously defined, 285 -NR 15 R 16 wherein R 15 and R 16 are as previously defined, =N-0-R 12 where R 12 is as previously defined, 'O-S(O)nRI 2 where n is 0, 1 or 2 and R 12 is as previously defined, aryl, 290 substituted aryl, (in) heteroaryl, substituted heteroaryl, C 3 -C 7 -cycloalkyl, CI-C 12 -alkyl substituted with heteroaryl, 295 NHC(O)RI 2 where R 12 is as previously defined, NHC(O)NR 13 RI 4 wherein R 13 and R 14 are as previously defined, =N-NR 15 RI 6 wherein R 15 and R 16 are as previously defined, -N-RI I wherein RI I is as previously defined, =N-NHC(O)Rl 2 where R 12 is as previously defined, 300 and -212- WO 97/42206 PCTIUS97/07702 =N-NHC(O)NR 13 R 14 wherein R 13 and R 14 are as previously defined; C 3 -C 10 -alkynyl; and S 305 C 3 -C10-alkynyl substituted with one or more substituents selected from the group consisting of trialkylsilyl, aryl, substituted aryl, 310 heteroaryl, and substituted heteroaryl; one of Y and Z is hydrogen and the other is selected from a group consisting of 315 hydrogen, hydroxy, protected hydroxy, and NR 7 R 8 wherein R 7 and R 8 are as defined above; 320 and A, B, D and E, with the provision that at least two of A, B, D and E are hydrogen, are independently selected from the group consisting of: 325 hydrogen; C 1 -C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of: aryl; (ii) substituted-aryl; 330 (iii) heteroaryl; (iv) substituted-heteroaryl; heterocycloalkyl; (vi) hydroxy; (vii) Ci-C6-alkoxy; 335 (viii) halogen consisting of Br, Cl, F or I; and (ix) NR 9 R 10 wherein R 9 and R 10 are as defined above; C 3 -C 7 -cycloalkyl; -213- WO 97/42206 PCTIUS97/07702 aryl; substituted-aryl; 340 heteroaryl; substituted-heteroaryl; heterocycloalkyl; and a group selected from option above further substituted with -M-RI 1 wherein M and R I are as defined above; 345 or any one pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7- membered ring optionally containing a hetero function selected from the group consisting of-O-, -N(CI-C 6 -alkyl-)-, -N(aryl-Cl-C6-alkyl-)-, 350 -N(substituted-aryl-C I -C 6 -alkyl-)-, -N(heteroaryl-C I -C 6 -alkyl-)-, -N(substituted-heteroary1-C1I-C6-alkyl+), or wherein n is 1 or 2, -C(O)-NR 12 wherein R 12 is as defined above, -NR 12 wherein R 12 is as defined above, and 355 is a method comprising: treating a compound having the formulae H Rp NMe 2 H RP NMe 2 V H I I. H I 6 .10 60 Ra 0 0 Ra 0*I 0 Rb 0O'. 0 Rb 0, 0 0 O-R1 360 Re R -214- .WO 97/42206 H RP NMe 2 H 6 04zr 0/4. 6 0 0 0 0 Rb 0' Rb RRc 0 0-R0 Re H RP NMe 2 Rg v vI I II S zz 0 6 R h 0 0 0 Rb 00, Rb 0 00 0 Re 365 D- BN~ H RP NMe 2 6 01 0 R b 00 0 Re;or PCTIUS97/07702 -2 WO 97/42206 WO 9742206PCT[US97/07702 I H RP NMe 2 00 Rb 00 0 Re 370 wherein RP is a hydroxy protecting group and V is =N-O-RI or =N-O-C(R 9 )(RIO%-O-RI wherein RI, R 9 and RIO are as defined above, with a base in an aprotic solvent then with an alkylating agent to give a compound having the formula y vR np rMe 2 RPR NMe 2 1 z0g,. 1 0," Ho,. 6 0 60 Ra 0 0i Ra 0*I 0 Rb 0 0 Rb 0,, 0 0 Re Re 375 -216- PCT1US97/07702 S, WO 97/42206 380 or wherein A, B, D, E, W, X, Y, Z, Ra, Rb, Rc, Rd, Re, Rf, R9 and Rh are as defined above, 385 V is =N-O-RI or =N-O-C(R 5 )(R 6 )-O-RI wherein R. 1 R 5 and R 6 are as defined above, and R is the "alkyl group" derived from the corresponding alkylating agent; deprotecting the and 4'-hydroxyl groups to give a compound of the formula -217- PCT[US97/07702 O WO 97/42206 OH RH NMe 2 6 HO,,, Ra 0 Ra,4 Rb 04' 0 Rb 0H 390 R OH R H NMe 2 6 0 0 C Rb 0".0Rb Rc Re OH R H NMe 2 Rg 0, I Rh0 Rb 0. R' Rc Re 395 -218- 2 19 DH NMe 2 R I A N I 0, B' OzzzK 0 b 0 Rb 0 0 0 0-H 0 Re ;or D H EH NMe 2 I R Bp 00, 0 R 0 R wheeinAB, D, E. W, X, Y, Z, R3, R, Re, Re, R9 and Rh are as defined above and R is the "alkyl group" derived from the corresponding alkylating agent; and deoxirnation with an inorganic sulfur oxide salt or an inorganic nitrite salt in a. the presence of acid in a suitable solvent to give the desired products. 24. A process for preparing a compound having the formulae (11) or (111) defined *in claim~ 1, comprising: treating a compound having a formula: R~N~ 2 H RP NMe 2 V H Iz.. HO0,. 6 R a 0o r R a 0 00 0 o b 0" R R 0 R c R 0R 00ORP ORP 00 Re 0 Re J R:\LIBXX]01361spcC.doceaak 219a wherein R, Rh, Rr, RP, Y and Z are defined in claim 1, wherein V is =N-0-Rl or wherein and R 6 are defined as in claim 1, with an alkylating agent to formu a compound having a formula: R P NMe2 y RP NMe2 V, R I 6 H 0 0 0 0 b 0 b 0 FR c O-RP O-RI deprotecting the and 4" -hydroxyl groups of the compound as obtained in step to form a compound having a formula: H NMe2 y H NMe2 V R I '00 0 6 Rq 0 or R 0 0 R 0 FR c R 0 Rc~ O-H 0 O-H R R and [RA\LIBXX]01361spec. doc:aak 220- optionally deoximating the compounds obtained in step with an inorganic SLILiu oxide salt or an inoroanic nitrite salt In the presence of acid. A process for preparing a compound of formula (IV) as defined in claim 1, Compr-ising1: treating a comipound having a formula: RP NMe 2 O R I 1 0, 6 0 HO, 0 0 0 b c R 0 Rc U Q-R~ \.her-ein R" is H or a hydroxy protecting group and R, Rc and R' are defined as in claim I\,vith formialdehyde in the presence of an acid or chloroiodomnethane in the presence of a hase to give a H, I1 2-mcthylenedioxy compound having a formula: RP NMe 2 o R I .0. 6 K02 o *a *00 *0 *4 .e 0.6. and deprotecting the and 4"-hydroxy protecting groups of' the compound obtained in step, 26. .A process for preparing a compound of formula as defined in claim 1, comprising: treating a compound having a formula: I I j-.b\j-jBXXj02267.d.c:aak HO0..,. HO.-. \\hcrefi K 1 1 Is I-I or- a hydroxy protecting gr-oup. and R. R h, R' and R' are defined as in claimn l Mith aI baIse tOllowed by reactioni with a reagent selected Crom the group con~sisting of phosgenie. diphosg)ene. triphosgene and benzylchlorol-brmate. to gi\e a compound having a 61 run uILa: R P NMe 2 0 R i &.e a a. 4 9 9 Oee* 6~ a. *4 4. a a. a. 9 a '~4 a 4 a a 2 a S. 9 a a. *0 a. 0 0 a *909 deprotecting the 2T and 4"-hydroxy protecting groups. 27, A process for preparing a compound of formula (VI) as defined in claim 1, lo comprisingl: treating a compou~nd having a formula: R~NMe 2 RP NMe 2 I :\I~ayLih\I. I 13X Xj02267.docaA 222 \whereinl R"1 is I-I or a hydroxy protecting group, and R, R't, R' and R' are defined in claim 1, w\ith a base and carbonyldiimidazole in an aprotic solvent to form a compound having a NMe 2 N\N N 0Rb hydrolIzIng to afford the compou~nd of 'Ormnula (VI). 28. A- process preparing a compound having the formula (VII) ais defined inclaim 1, Comprising: treating a compound having a formula: a.. a a a a a a a a. a 1, w\herein R is I-I or a hydroxy group and R, R R' and R' are defined as in claim 1, with a rec-ent selected fromn the grouIp consisting of an R NIh, hydrazine, R-P NNH 2 hyd roxy lamnine, 0-CI-C(,-alkylated hydroxy lamine, and R-C-10, wherein W, and R 4 are dlefined as in claim 1 to form a comrpound having a forl1a: I I \ay I ,\L1BX X102267 d- ank 223 wherein R" is H- or a hydroxy protecting group and R, R b, R" and W are defined as in clIai I rn1- and deprotecting the 2' and 4"-hydroxy protecting groups. 29. A- process for preparing a compound having a formula (VIII) as defined in claim Comnprisin": treating a compound having the formla: RP NMe 2 0 R I N 1 0, .0 N 6 0 0 0 0 R b 0 Rc 0 Re wvherein R" is hydrogen or a hydroxy protecting group, and R, Rb, and Rc are defined in claim 1, with a 1 ,2-diarnine compound having a formula: D R B' NH 2 w.herein R' is and A, B, D, and E are defined as In claim 1, to forml a compound of the formula: ED R' NMe 2 A, B N.. 0 =0 0 0 0 b 0 R 00Rc 0 Re O'and deprotecting the 2' and 4"hydroxy protecting groups. 9* C 9 9 9 *999 1Aflay.b\1- I1 BXX 102 267. doc aak 224 A process for preparing a compound having a formula (IX) as defined in claim I. comprising: treating a compound having the formula: ED R p NMe 2 *b 0 0-1R E O RR SOR" \\wheeI-in R j is hydrogen or a hydroxy protecting group, and A, B, D. E. R, Rc, and R' are del ined in claim 1, with a reducing agent to form a product having the formula: D H R RP NMe2 O O O O droen** hydroxy protecting group A RC 0 Re 'ORP deprotecting the and 4"-hydroxy protecting groups. 1. A compound of claim 1 and substantially as herein described with reference to the Examples. 32. A process of preparing a compound of claim I which process is substantially as herein described with reference to the Examples. S33. A compound of claim 1 when prepared by the process of claim 32. 34. A pharmaceutical composition for controlling a bacterial infection for a 1 mammal comprising a compound of claim 31 or 33 together with a pharmaceutically acceptable carrier. Use of a compound of claim 31 or 33 in the preparation of a medicament for controlling a bacterial infection in a mammal. SI\l)ayL.ib\LIBXXO02267.doc:aak 225 36. A method of controlling a bacterial infection in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of claim 31 or 33 or a composition of claim 34. Dated 1 August, 2000 Abbott Laboratories Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 9o (I:\DayLib\LIBXX]02267 doc:aak